Refolding dynamics of stretched biopolymers upon force quench (2009)
Hyeon, Changbong, Morrison, Greg, Pincus, David L., Thirumalai, D.
Single molecule force spectroscopy methods can be used to generate folding trajectories of biopolymers from arbitrary regions of the folding landscape. We illustrate the complexity of the folding...
Theory of biopolymer stretching at high forces (2009)
Toan, Ngo Minh, Thirumalai, D.
We provide a unified theory for the high force elasticity of biopolymers solely in terms of the persistence length, $\xi_p$, and the monomer spacing, $a$. When the force $f>\fh \sim k_BT\xi_p/a^2$...
M. S. Li, P. H. Nguyen, D. Thirumalai, Jan Meinke, Ipan Mohanty, ...
published in
From Computational Biophysics to Systems Biology (CBSB07), (2009)
C. Hyeon, D. Thirumalai, Jan Meinke, Ipan Mohanty, Olav Zimmermann (editors, ...
published in
O'Brien, E. P., Morrison, G., Brooks, B. R., Thirumalai, D.
Single molecule Forster resonance energy transfer (FRET) experiments are used to infer the properties of the denatured state ensemble (DSE) of proteins. From the measured average FRET efficiency, ,...
Crowding effects on the structural transitions in a flexible helical homopolymer (2009)
Kudlay, Alexander, Cheung, Margaret S., Thirumalai, D.
We elucidate the structural transitions in a helical off-lattice homopolymer induced by crowding agents, as function of the number of monomers ($N$) and volume fraction ($\phi_c$) of crowding...
Water-mediated interactions between hydrophobic and ionic species in cylindrical nanopores (2009)
Vaitheeswaran, S., Reddy, G., Thirumalai, D.
We use Metropolis Monte Carlo and umbrella sampling to calculate the free energies of interaction of two methane molecules and their charged derivatives in cylindrical water-filled pores. Confinement...
Probing the Mechanisms of Fibril Formation Using Lattice Models (2008)
Li, Mai Suan, Klimov, D. K., Straub, J. E., Thirumalai, D.
Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature and the number of chains. While these models are, at...
Crowding effects on the mechanical stability and unfolding pathways of Ubiquitin (2008)
Pincus, David L., Thirumalai, D.
The interior of cells is crowded thus making it important to assess the effects of macromolecules on the folding of proteins. Using the Self-Organized Polymer (SOP) model, which is a coarse-grained...
Compression and stretching of a self-avoiding chain in cylindrical nanopores (2008)
Jun, Suckjoon, Thirumalai, D., Ha, Bae-Yeun
Force-induced deformations of a self-avoiding chain confined inside a cylindrical cavity, with diameter $D$, are probed using molecular dynamics simulations, scaling analysis, and analytical...
Minimal models for proteins and RNA: From folding to function (2008)
Pincus, D. L., Cho, S. S., Hyeon, C., Thirumalai, D.
We present a panoramic view of the utility of coarse-grained (CG) models to study folding and functions of proteins and RNA. Drawing largely on the methods developed in our group over the last twenty...
Semiflexible Chains in Confined Spaces (2008)
Morrison, Greg, Thirumalai, D.
We develop an analytical method for studying the properties of a non-interacting Wormlike Chain (WLC) in confined geometries. The mean field-like theory replaces the rigid constraints of confinement...
Hyeon, Changbong, Morrison, Greg, Thirumalai, D.
The sequence-dependent folding landscapes of nucleic acid hairpins reflect much of the complexity of biomolecular folding. Folding trajectories, generated using single molecule force clamp...
The role of internal chain dynamics on the rupture kinetics of adhesive contacts (2008)
Barsegov, V., Morrison, G., Thirumalai, D.
We study the forced rupture of adhesive contacts between monomers that are not covalently linked in a Rouse chain. When the applied force ($f$) to the chain end is less than the critical force for...
Kinetics of Loop Formation in Polymer Chains (2007)
Toan, Ngo Minh, Morrison, Greg, Hyeon, Changbong, Thirumalai, D.
We investigate the kinetics of loop formation in flexible ideal polymer chains (Rouse model), and polymers in good and poor solvents. We show for the Rouse model, using a modification of the theory...
Chen, Jie, Dima, Ruxandra I., Thirumalai, D.
E. Coli. dihydrofolate reductase (DHFR) undergoes conformational transitions between the closed (CS) and occluded (OS) states which, respectively, describe whether the active site is closed or...
Stretching Homopolymers (2007)
Morrison, Greg, Hyeon, Changbong, Toan, N. M., Ha, Bae-Yeun, Thirumalai, D.
Force induced stretching of polymers is important in a variety of contexts. We have used theory and simulations to describe the response of homopolymers, with $N$ monomers, to force ($f$) in good and...
Effect of finite size on cooperativity and rates of protein folding (2006)
Kouza, Maksim, Li, Mai Suan, O'Brien Jr., Edward P., Hu, Chin-Kun, Thirumalai, D.
We analyze the dependence of cooperativity of the thermal denaturation transition and folding rates of globular proteins on the number of amino acid residues, $N$, using lattice models with side...
Hyeon, Changbong, Thirumalai, D.
Single molecule mechanical unfolding experiments are beginning to provide profiles of the complex energy landscape of biomolecules. In order to obtain reliable estimates of the energy landscape...
Dynamics of allosteric transitions in GroEL (2006)
Hyeon, Changbong, Lorimer, George H., Thirumalai, D.
The chaperonin GroEL-GroES, a machine which helps some proteins to fold, cycles through a number of allosteric states, the $T$ state, with high affinity for substrate proteins (SPs), the ATP-bound...
Pathways and kinetic barriers in mechanical unfolding and refolding of RNA and proteins (2006)
Hyeon, Changbong, Dima, Ruxandra I, Thirumalai, D.
Using self-organized polymer models, we predict mechanical unfolding and refolding pathways of ribo-zymes, and the green fluorescent protein. In agreement with experiments, there are between six and...
Size, shape, and flexibility of RNA structures (2006)
Hyeon, Changbong, Dima, Ruxandra I., Thirumalai, D.
Determination of sizes and flexibilities of RNA molecules is important in understanding the nature of packing in folded structures and in elucidating interactions between RNA and DNA or proteins....
Mechanical unfolding of RNA: From hairpins to structures with internal multiloops (2006)
Hyeon, Changbong, Thirumalai, D.
Mechanical unfolding of RNA structures, ranging from hairpins to ribozymes, using laser optical tweezer (LOT) experiments have begun to reveal the features of the energy landscape that cannot be...
Hydrophobic and Ionic Interactions in Nano-sized Water Droplets (2006)
Vaitheeswaran, S., Thirumalai, D.
We investigate the solvation of methane and methane decorated with charges in spherically confined water droplets. Free energy profiles for a single methane molecule in droplets, ranging in diameter...
Scenarios for protein aggregation: Molecular Dynamics simulations and Bioinformatic Analysis (2006)
Dima, Ruxandra I., Tarus, Bogdan, Straub, John E., Thirumalai, D.
The need to understand the assembly kinetics of fibril formation has become urgent because of the realization that soluble oligomers of amyloidogenic peptides may be even more neurotoxic than the end...
Forced-unfolding and force-quench refolding of RNA hairpins (2006)
Hyeon, Changbong, Thirumalai, D.
Using coarse-grained model we have explored forced-unfolding of RNA hairpin as a function of $f_S$ and the loading rate ($r_f$). The simulations and theoretical analysis have been done without and...
Kinetics of Interior Loop Formation in Semiflexible Chains (2006)
Hyeon, Changbong, Thirumalai, D.
Loop formation between monomers in the interior of semiflexible chains describes elementary events in biomolecular folding and DNA bending. We calculate analytically the interior distance...
Barsegov, V., Klimov, D., Thirumalai, D.
In the current AFM experiments the distribution of unfolding times, P(t), is measured by applying a constant stretching force f_s from which the apparent unfolding rate is obtained. To describe the...
Dynamic transition in tRNA is solvent induced (2006)
Caliskan, G, Briber, RM, Thirumalai, D, Garcia Sakai, V, Woodson, SA, Sokolov, AP
Dima, Ruxandra I., Thirumalai, D.
Allosteric interactions between residues that are spatially apart and well separated in sequence are important in the function of multimeric proteins as well as single-domain proteins. This...
Persistence Length Changes Dramatically as RNA Folds (2005)
Caliskan, G., Hyeon, C., Perez-Salas, U., Briber, R. M., Woodson, S. A., Thirumalai, D.
We determine the persistence length, $l_p$, for a bacterial group I ribozyme as a function of concentration of monovalent and divalent cations by fitting the distance distribution functions $P(r)$...
Influence of surface interactions on folding and forced unbinding of semiflexible chains (2005)
We investigate the folding and forced-unbinding transitions of adsorbed semiflexible polymer chains using theory and simulations. These processes describe biologically relevant phenomena that include...
Probing protein-protein interactions by dynamic force correlated spectroscopy (FCS) (2005)
We develop a formalism for single molecule dynamic force spectroscopy to map the energy landscape of protein-protein complex ($P_1$$P_2$). The joint distribution $P(\tau_1,\tau_2)$ of unbinding...
The shape of a flexible polymer in a cylindrical pore (2005)
We calculate the mean end-to-end distance ($R$) of a self-avoiding polymer encapsulated in an infinitely long cylinder with radius $D$. A self-consistent perturbation theory is used to calculate $R$...
Mechanical unfolding of RNA hairpins (2005)
Hyeon, Changbong, Thirumalai, D.
Mechanical unfolding trajectories, generated by applying constant force in optical tweezer experiments, show that RNA hairpins and the P5abc subdomain of the group I intron unfold reversibly. We use...
Access the most recent version at doi: 10.1110/ps.051767306 References (2005)
Ra I. Dima, D. Thirumalai, Email Alerting, Ruxandra I. Dima, D. Thirumalai
Determination of network of residues that regulate allostery in
Identifying natural substrates for chaperonins using a sequence-based approach (2005)
Stan, George, Brooks, Bernard R., Lorimer, George H., Thirumalai, D.
The Escherichia coli chaperonin machinery, GroEL, assists the folding of a number of proteins. We describe a sequence-based approach to identify the natural substrate proteins (SPs) for GroEL. Our...
Finite size effects on calorimetric cooperativity of two-state proteins (2004)
Li, Mai Suan, Klimov, D. K., Thirumalai, D.
Finite size effects on the calorimetric cooperatity of the folding-unfolding transition in two-state proteins are considered using the Go lattice models with and without side chains. We show that for...
Finite size effects on thermal denaturation of globular proteins (2004)
Li, Mai Suan, Klimov, D. K., Thirumalai, D.
Finite size effects on the cooperative thermal denaturation of proteins are considered. A dimensionless measure of cooperativity, Omega, scales as N^zeta, where N is the number of amino acids....
Proteins associated with diseases show enhanced sequence correlation between charged residues (2004)
Dima, Ruxandra I., Thirumalai, D.
Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of distant...
Proteins associated with diseases show enhanced sequence correlation between charged residues (2004)
Dima, Ruxandra I., Thirumalai, D.
Motivation: Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of...
Identifying natural substrates for chaperonins using a sequence-based approach (2004)
Stan, George, Brooks, Bernard R., Lorimer, George H., Thirumalai, D.
The Escherichia coli chaperonin machinery, GroEL, assists the folding of a number of proteins. We describe a sequence-based approach to identify the natural substrate proteins (SPs) for GroEL. Our...
Proteins associated with diseases show enhanced sequence correlation between charged residues (2004)
Dima, Ruxandra I., Thirumalai, D.
Motivation: Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of...
Proteins associated with diseases show enhanced sequence correlation between charged residues (2004)
Dima, Ruxandra I., Thirumalai, D.
Motivation: Function of proteins or a network of interacting proteins often involves communication between residues that are well separated in sequence. The classic example is the participation of...
Asymmetry in the shapes of folded and denatured states of proteins (2003)
Dima, Ruxandra I., Thirumalai, D.
The asymmetry in the shapes of folded and unfolded states are probed using two parameters, one being a measure of the sphericity and the other that describes the shape. For the folded states, whose...
Thermal denaturation and folding rates of single domain proteins: size matters (2003)
Li, Mai Suan, Klimov, D. K., Thirumalai, D.
We analyze the dependence of thermal denaturation transition and folding rates of globular proteins on the number of amino acid residues, N. Using lattice Go models we show that DeltaT/T_F ~ N^-1,...
We present a new method to extract distance and orientation dependent potentials between amino acid side chains using a database of protein structures and the standard Boltzmann device. The...
Dependence of folding rates on protein length (2002)
Li, Mai Suan, Klimov, D. K., Thirumalai, D.
Using three-dimensional Go lattice models with side chains for proteins, we investigate the dependence of folding times on protein length. In agreement with previous theoretical predictions, we find...
Folding in lattice models with side chains (2002)
Li, Mai Suan, Klimov, D. K., Thirumalai, D.
The folding kinetics of three-dimensional lattice Go models with side chains is studied using two different Monte Carlo move sets. A flexible move set based on single, double and triple backbone...
Bending rigidity of stiff polyelectrolyte chains: Single chain and a bundle of multichains (2002)
We study the bending rigidity of highly charged stiff polyelectrolytes, for both a single chain and many chains forming a bundle. A theory is developed to account for the interplay between...
Massi, Francesca, Klimov, D., Thirumalai, D., Straub, John E.
The activity of the Alzheimer's amyloid β-peptide is a sensitive function of the peptide's sequence. Increased fibril elongation rate of the E22Q Dutch mutant of the Alzheimer's amyloid β-peptide...
Many seemingly unrelated neurodegenerative disorders, such as amyloid and prion diseases, are associated with propagating fibrils whose structures are dramatically different from the native states of...
Introducing Protein Folding Using Simple Models (2001)
We discuss recent theoretical developments in the study of simple lattice models of proteins. Such models are designed to understand general features of protein structures and mechanism of folding....
Dynamics of Collapse of flexible Polyelectrolytes and Polyampholytes (2000)
We provide a theory for the dynamics of collapse of strongly charged polyelectrolytes (PEs) and flexible polyampholytes (PAs) using Langevin equation. After the initial stage, in which counterions...
Emergence of stable and fast folding protein structures (1999)
The number of protein structures is far less than the number of sequences. By imposing simple generic features of proteins (low energy and compaction) on all possible sequences we show that the...
Two Landmarks in Polymer Physics: The Edwards Model and de Gennes Observation (1999)
The impact of two landmark papers one by Edwards and the other by de Gennes on the field of polymer physics is highlighted.
The collapse kinetics of strongly charged polyelectrolytes in poor solvents is investigated by Langevin simulations and scaling arguments. The rate of collapse increases sharply as the valence of...
Stretching Single Domain Proteins: Phase Diagram and Kinetics of Force-Induced Unfolding (1999)
Single molecule force spectroscopy reveals unfolding of domains in titin upon stretching. We provide a theoretical framework for these experiments by computing the phase diagrams for force-induced...
Persistence Length of Flexible Polyelectrolyte Chains (1998)
We calculate the dependence of the electrostatic persistence length, l_e, of weakly charged flexible polyelectrolyte chains using a self-consistent variational theory. The variation of l_e with...
Stretching DNA: Role of electrostatic interaction (1998)
The effect of electrostatic interactions on the stretching of DNA is investigated using a simple worm like chain model. In the limit of small force there are large conformational fluctuations which...
Fractal Analysis of Protein Potential Energy Landscapes (1998)
Lidar, D. A., Thirumalai, D., Elber, R., Gerber, R. B.
The fractal properties of the total potential energy V as a function of time t are studied for a number of systems, including realistic models of proteins (PPT, BPTI and myoglobin). The fractal...
We investigate the sequence-dependent properties of proteins that determine the dual requirements of stability of the native state and its kinetic accessibility using simple cubic lattice models....
Cooperativity in Protein Folding: From Lattice Models with Side Chains to Real Proteins (1998)
We consider equilibrium folding transitions in lattice protein models with and without side chains. A dimensionless measure, $Omega_{c}$, is introduced to quantitatively assess the degree of...
Exploring Rugged Energy Landscape in Large Systems. (1997)
During this grant period we tackled three problems all related to systems with rugged energy landscape: (1) Developing replica molecular dynamics method to detect bottle-necks in energy surface; (2)...
Distribution Function of the End-to-End Distance of Semiflexible Polymers (1997)
Bhattacharjee, J. K., Thirumalai, D., Bryngelson, J. D.
The distribution function of the end-to-end distance of a semiflexible polymer, G(R;L) (where R denotes the end-to-end distance and L the contour length), is calculated using a meanfield-like...
Thermodynamic stability of folded proteins against mutations (1997)
Bussemaker, H. J., Thirumalai, D., Bhattacharjee, J. K.
By balancing the average energy gap with its typical change due to mutations for protein-like heteropolymers with M residues, we show that native states are unstable to mutations on a scale M* ~...
Viscosity Dependence of the Folding Rates of Proteins (1997)
The viscosity dependence of the folding rates for four sequences (the native state of three sequences is a beta-sheet, while the fourth forms an alpha-helix) is calculated for off-lattice models of...
Statistical Mechanics of Semiflexible Chains: A Meanfield Variational Approach (1997)
We describe a simple meanfield variational approach to study a number of properties of intrinsically stiff chains which are appropriate models for a large class of biopolymers. We present the...
Kinetic Partitioning Mechanism as a Unifying Theme in the Folding of Biomolecules (1997)
Thirumalai, D., Klimov, D. K., Woodson, S. A.
We present a unified framework for folding kinetics of proteins and RNA. The basis for this framework relies on the notion of topological frustration, which gives rise to several competing basins of...
A Kinetic Model for Chaperonin Assisted Folding of Proteins (1997)
A master equation formalism is used to account for the possible kinetic action of chaperonin assisted folding of proteins. The model is based on the assumption that chaperonins rescue misfolded...
Persistence Length of Intrinsically Stiff Polyampholyte Chains (1997)
We calculate the contribution, lPA, to the persistence length arising from charge fluctuations of an intrinsically stiff polyampholyte (PA) chain. The interaction between charges along the PA...
Shape of Confined Polymer Chains (1997)
Cordeiro, C., Molisana, M., Thirumalai, D.
We consider the problem of polymer chains confined between two parallel plates (a slit). The interactions between the polymer and the plates are assumed to be repulsive. A variational theory is used...
A Kinetic Model for Chaperonin Assisted Folding of Proteins (1997)
A master equation formalism is used to account for the possible kinetic action of chaperonin assisted folding of proteins. The model is based on the assumption that chaperonins rescue misfolded...
Persistence Length of Intrinsically Stiff Polyampholyte Chains (1997)
We calculate the contribution, lPA, to the persistence length arising from charge fluctuations of an intrinsically stiff polyampholyte (PA) chain. The interaction between charges along the PA...
Shape of Confined Polymer Chains (1997)
Cordeiro, C., Molisana, M., Thirumalai, D.
We consider the problem of polymer chains confined between two parallel plates (a slit). The interactions between the polymer and the plates are assumed to be repulsive. A variational theory is used...
A Kinetic Model for Chaperonin Assisted Folding of Proteins (1997)
A master equation formalism is used to account for the possible kinetic action of chaperonin assisted folding of proteins. The model is based on the assumption that chaperonins rescue misfolded...
Persistence Length of Intrinsically Stiff Polyampholyte Chains (1997)
We calculate the contribution, lPA, to the persistence length arising from charge fluctuations of an intrinsically stiff polyampholyte (PA) chain. The interaction between charges along the PA...
Shape of Confined Polymer Chains (1997)
Cordeiro, C., Molisana, M., Thirumalai, D.
We consider the problem of polymer chains confined between two parallel plates (a slit). The interactions between the polymer and the plates are assumed to be repulsive. A variational theory is used...
Veitshans, T., Klimov, D. K., Thirumalai, D.
The folding kinetics of a number of sequences for off-lattice continuum model of proteins is studied using Langevin simulations at two values of the friction coefficient. We show that there is a...
Factors Governing the Foldability of Proteins (1996)
We use a three dimensional cubic lattice model of proteins to study their properties that determine folding to the native state. The protein chain is modeled as a sequence of $N$ beads. The...
Semiflexible Chains under Tension (1996)
A functional integral formalism is used to derive the extension of a stiff chain subject to an external force. The force versus extension curves are calculated using a meanfield approach in which the...
Reply to Comment on "Criterion that Determines the Foldability of Proteins" (1996)
We point out that the correlation between folding times and $\sigma = (T_{\theta } - T_{f})/T_{\theta }$ in protein-like heteropolymer models where $T_{\theta }$ and $T_{f}$ are the collapse and...
A Criterion That Determines Fast Folding of Proteins: A Model Study (1996)
Camacho, Carlos J., Thirumalai, D.
We consider the statistical mechanics of a full set of two-dimensional protein-like heteropolymers, whose thermodynamics is characterized by the coil-to-globular ($T_\theta$) and the folding ($T_f$)...
Localization of a Polymer with Internal Constraints (1996)
Bryngelson, J. D., Thirumalai, D.
We argue that Kantor and Kardar's assertion that their simulation results contradict our criterion for the localization of a softly constrainted ideal polymer is incorrect. Our criterion is...
From Minimal Models to Real Proteins: Time Scales for Protein Folding Kinetics (1995)
The multipathway mechanism discovered using minimal protein models in conjunction with scaling arguments are used to obtain time scales for the various processes in the folding of real proteins. We...
The Cavity Approach for Metastable Glassy States Near Random First Order Phase Transitions (1995)
Kirkpatrick, T., Thirumalai, D.
It is shown that the cavity method developed to describe equilibrium states in the mean-field Ising glass spin glass model can be generalized to describe metastable states in the mean-field Potts...
From Minimal Models to Real Proteins: Time Scales for Protein Folding Kinetics (1995)
The multipathway mechanism discovered using minimal protein models in conjunction with scaling arguments are used to obtain time scales for the various processes in the folding of real proteins. We...
The Cavity Approach for Metastable Glassy States Near Random First Order Phase Transitions (1995)
Kirkpatrick, T., Thirumalai, D.
It is shown that the cavity method developed to describe equilibrium states in the mean-field Ising glass spin glass model can be generalized to describe metastable states in the mean-field Potts...
From Minimal Models to Real Proteins: Time Scales for Protein Folding Kinetics (1995)
The multipathway mechanism discovered using minimal protein models in conjunction with scaling arguments are used to obtain time scales for the various processes in the folding of real proteins. We...
The Cavity Approach for Metastable Glassy States Near Random First Order Phase Transitions (1995)
Kirkpatrick, T., Thirumalai, D.
It is shown that the cavity method developed to describe equilibrium states in the mean-field Ising glass spin glass model can be generalized to describe metastable states in the mean-field Potts...
Mechanisms and kinetics of β-hairpin formation
Thermodynamics and kinetics of off-lattice models with side chains for the β-hairpin fragment of immunoglobulin-binding protein and its variants are reported. For all properties (except refolding...
Native topology determines force-induced unfolding pathways in globular proteins
Single-molecule manipulation techniques reveal that stretching unravels individually folded domains in the muscle protein titin and the extracellular matrix protein tenascin. These elastic proteins...
Hydration for a series of hydrocarbons
Mountain, Raymond D., Thirumalai, D.
The hydrophobic hydration in a series of hydrocarbons is probed by using molecular dynamics simulations. The solutes considered range from methane to octane. Examination of the shapes of the...
Pan, Jie, Thirumalai, D., Woodson, Sarah A.
Folding of the Tetrahymena self-splicing RNA into its active conformation involves a set of discrete intermediate states. The Mg2+-dependent equilibrium transition from the intermediates to the...
Stretching single-domain proteins: Phase diagram and kinetics of force-induced unfolding
Single-molecule force spectroscopy reveals unfolding of domains in titin on stretching. We provide a theoretical framework for these experiments by computing the phase diagrams for force-induced...
Todd, M J, Lorimer, G H, Thirumalai, D
We develop a heuristic model for chaperonin-facilitated protein folding, the iterative annealing mechanism, based on theoretical descriptions of "rugged" conformational free energy landscapes for...
We propose a phenomenological theory that accounts for entropic effects due to loop formation to predict pathways in the kinetics of protein folding. The theory, the basis of which lies in multiple...
Exploring the energy landscape in proteins.
We present two methods to probe the energy landscape and motions of proteins in the context of molecular dynamics simulations of the helix-forming S-peptide of RNase A and the RNase A-3'-UMP...
Kinetics and thermodynamics of folding in model proteins.
Monte Carlo simulations on a class of lattice models are used to probe the thermodynamics and kinetics of protein folding. We find two transition temperatures: one at T theta, when chains collapse...
Metastability of the folded states of globular proteins.
The possibility that several metastable minima exist in which the folded forms of a polypeptide chain have similar structural characteristics but different energies is suggested. The validity of this...
Simulations of β-hairpin folding confined to spherical pores using distributed computing
Klimov, D. K., Newfield, D., Thirumalai, D.
We report the thermodynamics and kinetics of an off-lattice Go model β-hairpin from Ig-binding protein confined to an inert spherical pore. Confinement enhances the stability of the hairpin due to...
Hyeon, Changbong, Thirumalai, D.
By considering temperature effects on the mechanical unfolding rates of proteins and RNA, whose energy landscape is rugged, the question posed in the title is answered in the affirmative. Adopting a...
Aqueous urea solution destabilizes Aβ16–22 oligomers
Klimov, D. K., Straub, John E., Thirumalai, D.
We use long multiple trajectories generated by molecular dynamics simulations to probe the stability of oligomers of Aβ16–22 (KLVFFAE) peptides in aqueous urea solution. High concentration of urea...
Probing the instabilities in the dynamics of helical fragments from mouse PrPC
Dima, Ruxandra I., Thirumalai, D.
The first step in the formation of the protease resistant form (PrPSc) of prion proteins involves a conformational transition of the monomeric cellular form of PrPC to a more stable aggregation prone...
Dynamics of unbinding of cell adhesion molecules: Transition from catch to slip bonds
The unbinding dynamics of complexes involving cell-adhesion molecules depends on the specific ligands. Atomic force microscopy measurements have shown that for the specific P-selectin–P-selectin...
Molecular crowding enhances native state stability and refolding rates of globular proteins
Cheung, Margaret S., Klimov, Dmitri, Thirumalai, D.
The presence of macromolecules in cells geometrically restricts the available space for poplypeptide chains. To study the effects of macromolecular crowding on folding thermodynamics and kinetics, we...
Mechanical unfolding of RNA hairpins
Hyeon, Changbong, Thirumalai, D.
Mechanical unfolding trajectories, generated by applying constant force in optical-tweezer experiments, show that RNA hairpins and the P5abc subdomain of the group I intron unfold reversibly. We use...
Neurodegenerative diseases induced by transmissible spongiform encephalopathies are associated with prions. The most spectacular event in the formation of the infectious scrapie form, referred to as...
Pulling-Speed-Dependent Force-Extension Profiles for Semiflexible Chains
Lee, Nam-Kyung, Thirumalai, D.
We present theory and simulations to describe nonequilibrium stretching of semiflexible chains that serve as models of DNA molecules. Using a self-consistent dynamical variational approach, we...
Maximizing RNA folding rates: a balancing act.
Large ribozymes typically require very long times to refold into their active conformation in vitro, because the RNA is easily trapped in metastable misfolded structures. Theoretical models show that...
Ribosome exit tunnel can entropically stabilize α-helices
Ziv, Guy, Haran, Gilad, Thirumalai, D.
Several experiments have suggested that newly synthesized polypeptide chains can adopt helical structures deep within the ribosome exit tunnel. We hypothesize that confinement in the roughly...
Li, Mai Suan, Hu, Chin-Kun, Klimov, Dmitri K., Thirumalai, D.
Mechanical folding trajectories for polyproteins starting from initially stretched conformations generated by single-molecule atomic force microscopy experiments [Fernandez, J. M. & Li, H. (2004)...
Stan, George, Brooks, Bernard R., Lorimer, George H., Thirumalai, D.
We have used a bioinformatic approach to predict the natural substrate proteins for the Escherichia coli chaperonin GroEL based on two simple criteria. Natural substrate proteins should contain...
Zheng, Wenjun, Brooks, Bernard R., Thirumalai, D.
By representing the high-resolution crystal structures of a number of enzymes using the elastic network model, it has been shown that only a few low-frequency normal modes are needed to describe the...
Mechanisms and kinetics of β-hairpin formation
Thermodynamics and kinetics of off-lattice models with side chains for the β-hairpin fragment of immunoglobulin-binding protein and its variants are reported. For all properties (except refolding...
Native topology determines force-induced unfolding pathways in globular proteins
Single-molecule manipulation techniques reveal that stretching unravels individually folded domains in the muscle protein titin and the extracellular matrix protein tenascin. These elastic proteins...
Hydration for a series of hydrocarbons
Mountain, Raymond D., Thirumalai, D.
The hydrophobic hydration in a series of hydrocarbons is probed by using molecular dynamics simulations. The solutes considered range from methane to octane. Examination of the shapes of the...
Pan, Jie, Thirumalai, D., Woodson, Sarah A.
Folding of the Tetrahymena self-splicing RNA into its active conformation involves a set of discrete intermediate states. The Mg2+-dependent equilibrium transition from the intermediates to the...
Stretching single-domain proteins: Phase diagram and kinetics of force-induced unfolding
Single-molecule force spectroscopy reveals unfolding of domains in titin on stretching. We provide a theoretical framework for these experiments by computing the phase diagrams for force-induced...
Todd, M J, Lorimer, G H, Thirumalai, D
We develop a heuristic model for chaperonin-facilitated protein folding, the iterative annealing mechanism, based on theoretical descriptions of "rugged" conformational free energy landscapes for...
We propose a phenomenological theory that accounts for entropic effects due to loop formation to predict pathways in the kinetics of protein folding. The theory, the basis of which lies in multiple...
Exploring the energy landscape in proteins.
We present two methods to probe the energy landscape and motions of proteins in the context of molecular dynamics simulations of the helix-forming S-peptide of RNase A and the RNase A-3'-UMP...
Kinetics and thermodynamics of folding in model proteins.
Monte Carlo simulations on a class of lattice models are used to probe the thermodynamics and kinetics of protein folding. We find two transition temperatures: one at T theta, when chains collapse...
Metastability of the folded states of globular proteins.
The possibility that several metastable minima exist in which the folded forms of a polypeptide chain have similar structural characteristics but different energies is suggested. The validity of this...
Simulations of β-hairpin folding confined to spherical pores using distributed computing
Klimov, D. K., Newfield, D., Thirumalai, D.
We report the thermodynamics and kinetics of an off-lattice Go model β-hairpin from Ig-binding protein confined to an inert spherical pore. Confinement enhances the stability of the hairpin due to...
Hyeon, Changbong, Thirumalai, D.
By considering temperature effects on the mechanical unfolding rates of proteins and RNA, whose energy landscape is rugged, the question posed in the title is answered in the affirmative. Adopting a...
Aqueous urea solution destabilizes Aβ16–22 oligomers
Klimov, D. K., Straub, John E., Thirumalai, D.
We use long multiple trajectories generated by molecular dynamics simulations to probe the stability of oligomers of Aβ16–22 (KLVFFAE) peptides in aqueous urea solution. High concentration of urea...
Probing the instabilities in the dynamics of helical fragments from mouse PrPC
Dima, Ruxandra I., Thirumalai, D.
The first step in the formation of the protease resistant form (PrPSc) of prion proteins involves a conformational transition of the monomeric cellular form of PrPC to a more stable aggregation prone...
Dynamics of unbinding of cell adhesion molecules: Transition from catch to slip bonds
The unbinding dynamics of complexes involving cell-adhesion molecules depends on the specific ligands. Atomic force microscopy measurements have shown that for the specific P-selectin–P-selectin...
Molecular crowding enhances native state stability and refolding rates of globular proteins
Cheung, Margaret S., Klimov, Dmitri, Thirumalai, D.
The presence of macromolecules in cells geometrically restricts the available space for poplypeptide chains. To study the effects of macromolecular crowding on folding thermodynamics and kinetics, we...
Mechanical unfolding of RNA hairpins
Hyeon, Changbong, Thirumalai, D.
Mechanical unfolding trajectories, generated by applying constant force in optical-tweezer experiments, show that RNA hairpins and the P5abc subdomain of the group I intron unfold reversibly. We use...
Neurodegenerative diseases induced by transmissible spongiform encephalopathies are associated with prions. The most spectacular event in the formation of the infectious scrapie form, referred to as...
Pulling-Speed-Dependent Force-Extension Profiles for Semiflexible Chains
Lee, Nam-Kyung, Thirumalai, D.
We present theory and simulations to describe nonequilibrium stretching of semiflexible chains that serve as models of DNA molecules. Using a self-consistent dynamical variational approach, we...
Ribosome exit tunnel can entropically stabilize α-helices
Ziv, Guy, Haran, Gilad, Thirumalai, D.
Several experiments have suggested that newly synthesized polypeptide chains can adopt helical structures deep within the ribosome exit tunnel. We hypothesize that confinement in the roughly...
Li, Mai Suan, Hu, Chin-Kun, Klimov, Dmitri K., Thirumalai, D.
Mechanical folding trajectories for polyproteins starting from initially stretched conformations generated by single-molecule atomic force microscopy experiments [Fernandez, J. M. & Li, H. (2004)...
Maximizing RNA folding rates: a balancing act.
Large ribozymes typically require very long times to refold into their active conformation in vitro, because the RNA is easily trapped in metastable misfolded structures. Theoretical models show that...
Stan, George, Brooks, Bernard R., Lorimer, George H., Thirumalai, D.
We have used a bioinformatic approach to predict the natural substrate proteins for the Escherichia coli chaperonin GroEL based on two simple criteria. Natural substrate proteins should contain...
Zheng, Wenjun, Brooks, Bernard R., Thirumalai, D.
By representing the high-resolution crystal structures of a number of enzymes using the elastic network model, it has been shown that only a few low-frequency normal modes are needed to describe the...
Barsegov, V., Klimov, D. K., Thirumalai, D.
We present, to our knowledge, a new theory that takes internal dynamics of proteins into account to describe forced-unfolding and force-quench refolding in single molecule experiments. In the current...
Dynamics of allosteric transitions in GroEL
Hyeon, Changbong, Lorimer, George H., Thirumalai, D.
The chaperonin GroEL-GroES, a machine that helps proteins to fold, cycles through a number of allosteric states, the T state, with high affinity for substrate proteins, the ATP-bound R state, and the...
Monomer adds to preformed structured oligomers of Aβ-peptides by a two-stage dock–lock mechanism
Nguyen, Phuong H., Li, Mai Suan, Stock, Gerhard, Straub, John E., Thirumalai, D.
Nonfibrillar soluble oligomers, which are intermediates in the transition from monomers to amyloid fibrils, may be the toxic species in Alzheimer's disease. To monitor the early events that direct...
Coupling between allosteric transitions in GroEL and assisted folding of a substrate protein
Stan, George, Lorimer, George H., Thirumalai, D., Brooks, Bernard R.
Escherichia coli chaperonin, GroEL, helps proteins fold under nonpermissive conditions. During the reaction cycle, GroEL undergoes allosteric transitions in response to binding of a substrate protein...
Mechanical Unfolding of RNA: From Hairpins to Structures with Internal Multiloops
Hyeon, Changbong, Thirumalai, D.
Mechanical unfolding of RNA structures, ranging from hairpins to ribozymes, using laser optical tweezer experiments have begun to reveal the features of the energy landscape that cannot be easily...
Denaturants can accelerate folding rates in a class of globular proteins.
Camacho, C. J., Thirumalai, D.
We present a lattice Monte Carlo study to examine the effect of denaturants on the folding rates of simplified models of proteins. The two-dimensional model is made from a three-letter code mimicking...
Betancourt, M. R., Thirumalai, D.
We examine the similarities and differences between two widely used knowledge-based potentials, which are expressed as contact matrices (consisting of 210 elements) that gives a scale for interaction...
Dima, Ruxandra I., Thirumalai, D.
Allosteric interactions between residues that are spatially apart and well separated in sequence are important in the function of multimeric proteins as well as single-domain proteins. This...
Identifying natural substrates for chaperonins using a sequence-based approach
Stan, George, Brooks, Bernard R., Lorimer, George H., Thirumalai, D.
The Escherichia coli chaperonin machinery, GroEL, assists the folding of a number of proteins. We describe a sequence-based approach to identify the natural substrate proteins (SPs) for GroEL. Our...
Exploring protein aggregation and self-propagation using lattice models: Phase diagram and kinetics
Many seemingly unrelated neurodegenerative disorders, such as amyloid and prion diseases, are associated with propagating fibrils whose structures are dramatically different from the native states of...
Massi, Francesca, Klimov, D., Thirumalai, D., Straub, John E.
The activity of the Alzheimer's amyloid β-peptide is a sensitive function of the peptide's sequence. Increased fibril elongation rate of the E22Q Dutch mutant of the Alzheimer's amyloid β-peptide...
Mickler, Moritz, Dima, Ruxandra I., Dietz, Hendrik, Hyeon, Changbong, Thirumalai, D., Rief, Matthias
Nanomanipulation of biomolecules by using single-molecule methods and computer simulations has made it possible to visualize the energy landscape of biomolecules and the structures that are sampled...
Zheng, Wenjun, Brooks, Bernard R., Thirumalai, D.
The Escherichia coli chaperonin GroEL, which helps proteins to fold, consists of two heptameric rings stacked back-to-back. During the reaction cycle GroEL undergoes a series of allosteric...
Hyeon, Changbong, Morrison, Greg, Thirumalai, D.
The sequence-dependent folding landscapes of nucleic acid hairpins reflect much of the complexity of biomolecular folding. Folding trajectories, generated by using single-molecule force-clamp...
O'Brien, Edward P., Ziv, Guy, Haran, Gilad, Brooks, Bernard R., Thirumalai, D.
Interactions between denaturants and proteins are commonly used to probe the structures of the denatured state ensemble and their stabilities. Osmolytes, a class of small intracellular organic...
Hua, Lan, Zhou, Ruhong, Thirumalai, D., Berne, B. J.
The mechanism of denaturation of proteins by urea is explored by using all-atom microseconds molecular dynamics simulations of hen lysozyme generated on BlueGene/L. Accumulation of urea around...
Vaitheeswaran, S., Thirumalai, D.
Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and...
Probing the mechanisms of fibril formation using lattice models
Li, Mai Suan, Klimov, D. K., Straub, J. E., Thirumalai, D.
Using exhaustive Monte Carlo simulations we study the kinetics and mechanism of fibril formation using lattice models as a function of temperature (T) and the number of chains (M). While these models...