Vijay Pande
Stanford University, Chemistry, Faculty Member
We extend the theory of hybrid explicit implicit solvent models to include an explicit domain that grows and shrinks in response to a solute's evolving configuration. The goal of this model is to provide an appropriate but not excessive... more
We extend the theory of hybrid explicit implicit solvent models to include an explicit domain that grows and shrinks in response to a solute's evolving configuration. The goal of this model is to provide an appropriate but not excessive amount of solvent detail, and the inclusion of an adjustable boundary provides a significant computational advantage for solutes that explore a range of configurations. In addition to the theoretical development, a successful implementation of this method requires (1) an efficient moveset that propagates the boundary as a new coordinate of the system, and (2) an accurate continuum solvent model with parameters that are transferable to an explicit domain of any size. We address these challenges and develop boundary updates using Monte Carlo moves biased by nonequilibrium paths. We obtain the desired level of accuracy using a "decoupling interface" that we have previously shown to remove boundary artifacts common to hybrid solvent models. Using an uncharged, coarse-grained solvent model, we then study the efficiency of nonequilibrium paths that a simulation takes by quantifying the dissipation. In the spirit of optimization, we study this quantity over a range of simulation parameters.
To understand the kinetics of protein folding, we introduce the concept of a “transition coordinate” which is defined to be the coordinate along which the system progresses most slowly. As a practical implementation of this concept, we... more
To understand the kinetics of protein folding, we introduce the concept of a “transition coordinate” which is defined to be the coordinate along which the system progresses most slowly. As a practical implementation of this concept, we define the transmission coefficient for any conformation to be the probability for a chain with the given conformation to fold before it unfolds.
ABSTRACT Here, we summarize the assessment of protein structure refinement in CASP8. Twentyfour groups refined a total of 12 target proteins. Averaging over all groups and all proteins, there was no net improvement over the original... more
ABSTRACT Here, we summarize the assessment of protein structure refinement in CASP8. Twentyfour groups refined a total of 12 target proteins. Averaging over all groups and all proteins, there was no net improvement over the original starting models. However, there are now some individual research groups who consistently do improve protein structures relative to a starting starting model.
We present a technique for biomolecular free energy calculations that exploits highly parallelized sampling to significantly reduce the time to results. The technique combines free energies for multiple, nonoverlapping configurational... more
We present a technique for biomolecular free energy calculations that exploits highly parallelized sampling to significantly reduce the time to results. The technique combines free energies for multiple, nonoverlapping configurational macrostates and is naturally suited to distributed computing. We describe a methodology that uses this technique with docking, molecular dynamics, and free energy perturbation to compute absolute free energies of binding quickly compared to previous methods.
Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and... more
Membrane fusion is essential to both cellular vesicle trafficking and infection by enveloped viruses. While the fusion protein assemblies that catalyze fusion are readily identifiable, the specific activities of the proteins involved and nature of the membrane changes they induce remain unknown. Here, we use many atomic-resolution simulations of vesicle fusion to examine the molecular mechanisms for fusion in detail.
Recent analytic theories and computer simulations of heteropolymers have centered on the freezing transition of globular heteropolymers. We present a simple analytic theory to describe the coil to globule collapse in heteropolymers and... more
Recent analytic theories and computer simulations of heteropolymers have centered on the freezing transition of globular heteropolymers. We present a simple analytic theory to describe the coil to globule collapse in heteropolymers and compare this to the computer simulation of the exhaustive enumeration of all 18-mer cubic lattice polymer conformations. We find that the collapse transition from coil to frozen globule can either be first or second order.
Parallel tempering (PT) molecular dynamics simulations have been extensively investigated as a means of efficient sampling of the configurations of biomolecular systems. Recent work has demonstrated how the short physical trajectories... more
Parallel tempering (PT) molecular dynamics simulations have been extensively investigated as a means of efficient sampling of the configurations of biomolecular systems. Recent work has demonstrated how the short physical trajectories generated in PT simulations of biomolecules can be used to construct the Markov models describing biomolecular dynamics at each simulated temperature.
Abstract A common theme of studies using molecular simulation is a necessary compromise between computational efficiency and resolution of the forcefield that is used. Significant efforts have been directed at combining multiple levels of... more
Abstract A common theme of studies using molecular simulation is a necessary compromise between computational efficiency and resolution of the forcefield that is used. Significant efforts have been directed at combining multiple levels of granularity within a single simulation in order to maintain the efficiency of coarse-grained models, while using finer resolution in regions where such details are expected to play an important role.
Abstract Recently, a model for the preparation of" protein-like" heteropolymers with a unique and stable ground state has been proposed and examined computationally. Formally, this model is similar to another recently proposed and... more
Abstract Recently, a model for the preparation of" protein-like" heteropolymers with a unique and stable ground state has been proposed and examined computationally. Formally, this model is similar to another recently proposed and computationally examined model of the evolutionary design of protein-like heteropolymers. Using mean field replica theory, we find, in addition to the freezing transition of random chains, a transition to the target" native" state.
In 2003, the US National Human Genome Research Institute (NHGRI) articulated grand challenges for the genomics community in which the translation of genome-based knowledge into disease understanding, diagnostics, prognostics, drug... more
In 2003, the US National Human Genome Research Institute (NHGRI) articulated grand challenges for the genomics community in which the translation of genome-based knowledge into disease understanding, diagnostics, prognostics, drug response and clinical therapy is one of the three fundamental directions (" genomics to biology,"" genomics to health" and" genomics to society").
Transient and low-affinity protein complexes pose a challenge to existing experimental methods and traditional computational techniques for structural determination. One example of such a disordered complex is that formed by trimers of... more
Transient and low-affinity protein complexes pose a challenge to existing experimental methods and traditional computational techniques for structural determination. One example of such a disordered complex is that formed by trimers of influenza virus fusion peptide inserted into a host cell membrane. This fusion peptide is responsible for mediating viral infection, and spectroscopic data suggest that the peptide forms loose multimeric associations that are important for viral infectivity.
Proteins and other macromolecules have coupled dynamics over multiple time scales (from femtosecond to millisecond and beyond) that make resolving molecular dynamics challenging. We present an approach based on periodically decomposing... more
Proteins and other macromolecules have coupled dynamics over multiple time scales (from femtosecond to millisecond and beyond) that make resolving molecular dynamics challenging. We present an approach based on periodically decomposing the dynamics of a macromolecule into slow and fast modes based on a scalable coarse-grained normal mode analysis. A Langevin equation is used to propagate the slowest degrees of freedom while minimizing the nearly instantaneous degrees of freedom.
Algorithms for several emerging large-scale problems in cheminformatics have as their rate-limiting step the evaluation of relatively slow chemical similarity measures, such as structural similarity or three-dimensional (3-D) shape... more
Algorithms for several emerging large-scale problems in cheminformatics have as their rate-limiting step the evaluation of relatively slow chemical similarity measures, such as structural similarity or three-dimensional (3-D) shape comparison. In this article we present SCISSORS, a linear-algebraical technique (related to multidimensional scaling and kernel principal components analysis) to rapidly estimate chemical similarities for several popular measures.
As nascent proteins are synthesized by the ribosome, they depart via an exit tunnel running through the center of the large subunit. The exit tunnel likely plays an important part in various aspects of translation. Although water plays a... more
As nascent proteins are synthesized by the ribosome, they depart via an exit tunnel running through the center of the large subunit. The exit tunnel likely plays an important part in various aspects of translation. Although water plays a key role in many bio-molecular processes, the nature of water confined to the exit tunnel has remained unknown. Furthermore, solvent in biological cavities has traditionally been characterized as either a continuous dielectric fluid, or a discrete tightly bound molecule.
Enhanced production of a 42-residue beta amyloid peptide (Aβ 42) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not... more
Enhanced production of a 42-residue beta amyloid peptide (Aβ 42) in affected parts of the brain has been suggested to be the main causative factor for the development of Alzheimer's Disease (AD). The severity of the disease depends not only on the amount of the peptide but also its conformational transition leading to the formation of oligomeric amyloid-derived diffusible ligands (ADDLs) in the brain of AD patients.
We present a simple model of protein folding dynamics that captures key qualitative elements recently seen in all-atom simulations. The goals of this theory are to serve as a simple formalism for gaining deeper insight into the physical... more
We present a simple model of protein folding dynamics that captures key qualitative elements recently seen in all-atom simulations. The goals of this theory are to serve as a simple formalism for gaining deeper insight into the physical properties seen in detailed simulations as well as to serve as a model to easily compare why these simulations suggest a different kinetic mechanism than previous simple models.
Accurate and efficient methods to simulate biomolecular systems at multiple levels of detail simultaneously are an ongoing challenge for the simulation community. Here we present a new method for multi-scale simulation where a complex... more
Accurate and efficient methods to simulate biomolecular systems at multiple levels of detail simultaneously are an ongoing challenge for the simulation community. Here we present a new method for multi-scale simulation where a complex system can be partitioned into two loosely-coupled sub-systems, one coarse-grained and one atomistic.
Markov state models have been widely used to study conformational changes of biological macromolecules. These models are built from short timescale simulations and then propagated to extract long timescale dynamics. However, the solvent... more
Markov state models have been widely used to study conformational changes of biological macromolecules. These models are built from short timescale simulations and then propagated to extract long timescale dynamics. However, the solvent information in molecular simulations are often ignored in current methods, because of the large number of solvent molecules in a system and the indistinguishability of solvent molecules upon their exchange.
Abstract: While seemingly straightforward in principle, the reliable estimation of rate constants is seldom easy in practice. Numerous issues, such as the complication of poor reaction coordinates, cause obvious approaches to yield... more
Abstract: While seemingly straightforward in principle, the reliable estimation of rate constants is seldom easy in practice. Numerous issues, such as the complication of poor reaction coordinates, cause obvious approaches to yield unreliable estimates. When a reliable order parameter is available, the reactive flux theory of Chandler allows the rate constant to be extracted from the plateau region of an appropriate reactive flux function.
Abstract For decades, researchers have been applying computer simulation to address problems in biology. However, many of these—grand challenges “in computational biology, such as simulating how proteins fold, remained unsolved due to... more
Abstract For decades, researchers have been applying computer simulation to address problems in biology. However, many of these—grand challenges “in computational biology, such as simulating how proteins fold, remained unsolved due to their great complexity. Indeed, even to simulate the fastest folding protein would require decades on the fastest modern CPUs. Here, we review novel methods to fundamentally speed such previously intractable problems using a new computational paradigm: distributed computing.
Simulating protein folding has been a challenging problem for decades due to the long timescales involved (compared with what is possible to simulate) and the challenges of gaining insight from the complex nature of the resulting... more
Simulating protein folding has been a challenging problem for decades due to the long timescales involved (compared with what is possible to simulate) and the challenges of gaining insight from the complex nature of the resulting simulation data. Markov State Models (MSMs) present a means to tackle both of these challenges, yielding simulations on experimentally relevant timescales, statistical significance, and coarse grained representations that are readily humanly understandable.
We have developed a novel computational alanine scanning approach that involves analysis of ensemble unfolding kinetics at high temperature to identify residues that are critical for the stability of a given protein. This approach has... more
We have developed a novel computational alanine scanning approach that involves analysis of ensemble unfolding kinetics at high temperature to identify residues that are critical for the stability of a given protein. This approach has been applied to dimerization of the oligomerization domain (residues 326–355) of tumor suppressor p53. As validated by experimental results, our approach has reasonable success in identifying deleterious mutations, including mutations that have been linked to cancer.
Understanding cellular membrane processes is critical for the study of events such as viral entry, neurotransmitter exocytosis, and immune activation. Supported lipid bilayers are commonly used to model these membrane processes... more
Understanding cellular membrane processes is critical for the study of events such as viral entry, neurotransmitter exocytosis, and immune activation. Supported lipid bilayers are commonly used to model these membrane processes experimentally. Despite the relative simplicity of such a system, many important structural and dynamic parameters are not experimentally observable with current techniques. Computational approaches allow the development of a high-resolution model of bilayer processes.
Water plays a unique role in all living organisms. Not only is it nature's ubiquitous solvent, but it also actively takes part in many cellular processes. In particular, the structure and properties of interfacial water near biomolecules... more
Water plays a unique role in all living organisms. Not only is it nature's ubiquitous solvent, but it also actively takes part in many cellular processes. In particular, the structure and properties of interfacial water near biomolecules such as proteins are often related to the function of the respective molecule. It can therefore be highly instructive to study the local water density around solutes in cellular systems, particularly when solvent-mediated forces such as the hydrophobic effect are relevant.
Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ c). Here we found that in the structure of the IL-15–IL-15R α–IL-2Rβ–γ c... more
Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rβ and the common γ-chain (γ c). Here we found that in the structure of the IL-15–IL-15R α–IL-2Rβ–γ c quaternary complex, IL-15 binds to IL-2Rβ and γ c in a heterodimer nearly indistinguishable from that of the IL-2–IL-2R α–IL-2Rβ–γ c complex, despite their different receptor-binding chemistries.
Abstract: We investigate the rate-length scaling law of protein folding, a key undetermined scaling law in the analytical theory of protein folding. We demonstrate that chain length is a dominant factor determining folding times, and that... more
Abstract: We investigate the rate-length scaling law of protein folding, a key undetermined scaling law in the analytical theory of protein folding. We demonstrate that chain length is a dominant factor determining folding times, and that the unambiguous determination of the way chain length corre-lates with folding times could provide key mechanistic insight into the folding process.
Abstract Dynamical averages based on functionals of dynamical trajectories, such as time-correlation functions, play an important role in determining kinetic or transport properties of matter. At temperatures of interest, the expectations... more
Abstract Dynamical averages based on functionals of dynamical trajectories, such as time-correlation functions, play an important role in determining kinetic or transport properties of matter. At temperatures of interest, the expectations of these quantities are often dominated by contributions from rare events, making the precise calculation of these quantities by molecular dynamics simulation difficult.
The immunostimulatory cytokine interleukin-2 (IL-2) is a growth factor for a wide range of leukocytes, including T cells and natural killer (NK) cells. Considerable effort has been invested in using IL-2 as a therapeutic agent for a... more
The immunostimulatory cytokine interleukin-2 (IL-2) is a growth factor for a wide range of leukocytes, including T cells and natural killer (NK) cells. Considerable effort has been invested in using IL-2 as a therapeutic agent for a variety of immune disorders ranging from AIDS to cancer. However, adverse effects have limited its use in the clinic. On activated T cells, IL-2 signals through a quaternary 'high affinity' receptor complex consisting of IL-2, IL-2Rα (termed CD25), IL-2Rβ and IL-2Rγ. Naive T cells express only a low density of IL-2Rβ and IL-2Rγ, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rβ and IL-2Rγ. Here, using in vitro evolution, we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 'superkine' (also called super-2) with increased binding affinity for IL-2Rβ. Crystal structures of the IL-2 superkine in free and receptor-bound forms showed that the evolved mutations are principally in the core of the cytokine, and molecular dynamics simulations indicated that the evolved mutations stabilized IL-2, reducing the flexibility of a helix in the IL-2Rβ binding site, into an optimized receptor-binding conformation resembling that when bound to CD25. The evolved mutations in the IL-2 superkine recapitulated the functional role of CD25 by eliciting potent phosphorylation of STAT5 and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, the IL-2 superkine induced superior expansion of cytotoxic T cells, leading to improved antitumour responses in vivo, and elicited proportionally less expansion of T regulatory cells and reduced pulmonary oedema. Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy.
Abstract: Molecular dynamics algorithms are subject to some amount of error dependent on the size of the time step that is used. This error can be corrected by periodically updating the system with a Metropolis criteria, where the... more
Abstract: Molecular dynamics algorithms are subject to some amount of error dependent on the size of the time step that is used. This error can be corrected by periodically updating the system with a Metropolis criteria, where the integration step is treated as a selection probability for candidate state generation. Such a method, closely related to generalized hybrid Monte Carlo (GHMC), satisfies the balance condition by imposing a reversal of momenta upon candidate rejection.
The SCISSORS method for approximating chemical similarities has shown excellent empirical performance on a number of real-world chemical data sets but lacks theoretically proven bounds on its worst-case error performance. This paper first... more
The SCISSORS method for approximating chemical similarities has shown excellent empirical performance on a number of real-world chemical data sets but lacks theoretically proven bounds on its worst-case error performance. This paper first proves reductions showing SCISSORS to be equivalent to two previous kernel methods: kernel principal components analysis and the rank-k Nyström approximation of a Gram matrix.
Abstract. A massively parallel supercamputer was nsed to exhaustively enumerate all of the Hamiltonian walks for simple cubic sublattices of four different sires (up to 3 x 4 x 4). The behaviour of the logarithm of the number of walks was... more
Abstract. A massively parallel supercamputer was nsed to exhaustively enumerate all of the Hamiltonian walks for simple cubic sublattices of four different sires (up to 3 x 4 x 4). The behaviour of the logarithm of the number of walks was found to be linear in the number of vertices in the lattice. The linear fit is shown to agree also with the asymptotic limit of the Floy mean field theoretical estimate Thus, we suggest that the fit obtained yields the number of walks for any size fragment of the cubic Imice to logarithmic accuracy.
In this chapter we present the design and optimization of GPU implementations of two popular chemical similarity techniques: Gaussian shape overlay (GSO) and LINGO. GSO involves a data-parallel, arithmetically intensive iterative... more
In this chapter we present the design and optimization of GPU implementations of two popular chemical similarity techniques: Gaussian shape overlay (GSO) and LINGO. GSO involves a data-parallel, arithmetically intensive iterative numerical optimization; we use it to examine issues of thread parallelism, arithmetic optimization, and CPU-GPU transfer overhead minimization.
The ribosome is a large macromolecular machine, and correlated motion between residues is necessary for coordinating function across multiple protein and RNA chains. We ran two all-atom, explicit solvent molecular dynamics simulations of... more
The ribosome is a large macromolecular machine, and correlated motion between residues is necessary for coordinating function across multiple protein and RNA chains. We ran two all-atom, explicit solvent molecular dynamics simulations of the bacterial ribosome and calculated correlated motion between residue pairs by using mutual information. Because of the short timescales of our simulation (ns), we expect that dynamics are largely local fluctuations around the crystal structure.
Abstract The ability to create synthetic heteropolymers with the protein-like capabilities of renaturation to a particular conformation capable of specific molecular recognition is of great technological importance. To create protein-like... more
Abstract The ability to create synthetic heteropolymers with the protein-like capabilities of renaturation to a particular conformation capable of specific molecular recognition is of great technological importance. To create protein-like heteropolymers, we suggest" Imprinting," which dictates that monomers should be equilibrated at some low temperature prior to polymerization, then polymerized such that this monomer prearrangement is somewhat preserved.
Membrane fusion is a funda-mental process in neurotransmission, vesicle trafficking, and infection by enveloped viruses. Mutational studies of class I viral fusion proteins have shown that simply pulling the two membranes together is not... more
Membrane fusion is a funda-mental process in neurotransmission, vesicle trafficking, and infection by enveloped viruses. Mutational studies of class I viral fusion proteins have shown that simply pulling the two membranes together is not sufficient (1–3) to catalyze fusion in a physiological context: in these systems, a specific activity of the membrane-inserted peptides is required for full fusion. The precise mechanism of membrane activity has remained elusive.
Influenza virus attaches to and infects target cells via binding of cell-surface glycans by the viral hemagglutinin. This binding specificity is considered a major reason why avian influenza is typically poorly transmitted between humans,... more
Influenza virus attaches to and infects target cells via binding of cell-surface glycans by the viral hemagglutinin. This binding specificity is considered a major reason why avian influenza is typically poorly transmitted between humans, while swine influenza is better transmitted due to glycan similarity between the human and swine upper respiratory tract. Predicting mutations that control glycan binding is thus important to continued surveillance against new pandemic influenza strains.
Abstract Biomolecular simulation is a core application on supercomputers, but it is exceptionally difficult to achieve the strong scaling necessary to reach biologically relevant timescales. Here, we present a new paradigm for parallel... more
Abstract Biomolecular simulation is a core application on supercomputers, but it is exceptionally difficult to achieve the strong scaling necessary to reach biologically relevant timescales. Here, we present a new paradigm for parallel adaptive molecular dynamics and a publicly available implementation: Copernicus.
We present a new multiscale method that combines all-atom molecular dynamics with coarse-grained sampling, towards the aim of bridging two levels of physiology: the atomic scale of protein side chains and small molecules, and the huge... more
We present a new multiscale method that combines all-atom molecular dynamics with coarse-grained sampling, towards the aim of bridging two levels of physiology: the atomic scale of protein side chains and small molecules, and the huge scale of macromolecular complexes like the ribosome. Our approach uses all-atom simulations of peptide (or other ligand) fragments to calculate local 3D spatial potentials of mean force (PMF).
Abstract The dynamical and equilibrium properties of a strongly-coupled chain of charged particles (polyampholyte) submerged in a viscous medium are studied using the molecular dynamics simulations. The polyampholyte relaxes to an... more
Abstract The dynamical and equilibrium properties of a strongly-coupled chain of charged particles (polyampholyte) submerged in a viscous medium are studied using the molecular dynamics simulations. The polyampholyte relaxes to an equilibrium conformation typically in 300a»" 1 due to folding of the chain for low temperatures, and expands several times faster for high temperatures, where uave is the plasma frequency.
Abstract. Recently, a procedure to create renaturable hetempolymirs.'imprinting', has been proposed and examined theoretically. The significance of imprinting is, that certain aspects of a hetempolymer's native conformation may be mnmlled... more
Abstract. Recently, a procedure to create renaturable hetempolymirs.'imprinting', has been proposed and examined theoretically. The significance of imprinting is, that certain aspects of a hetempolymer's native conformation may be mnmlled during the synthesis stage. We examine this possibility theoretiully by introducing an extemal held during the synthesis and renaturation stages of the model.
The mechanism by which the aqueous cosolvents guanidinium chloride and urea denature proteins is a matter of controversy. Here, we use all-atom molecular dynamics simulations to study the effect of both denaturants on the dewetting of... more
The mechanism by which the aqueous cosolvents guanidinium chloride and urea denature proteins is a matter of controversy. Here, we use all-atom molecular dynamics simulations to study the effect of both denaturants on the dewetting of water confined between nanoseparated hydrophobic plates. It is found that the denaturants inhibit the onset of dewetting, so that it occurs at shorter interplate distances than in pure water.
Abstract Physics-based simulation is needed to understand the function of biological structures and can be applied across a wide range of scales, from molecules to organisms. Simbios (the national center for physics-based simulation of... more
Abstract Physics-based simulation is needed to understand the function of biological structures and can be applied across a wide range of scales, from molecules to organisms. Simbios (the national center for physics-based simulation of biological structures, http://www. simbios. stanford. edu/</weblink>) is one of seven NIH-supported national centers for biomedical computation. This article provides an overview of the mission and achievements of Simbios, and describes its place within systems biology.
Abstract: Commercial graphics processors (GPUs) have high compute capacity at very low cost, which makes them attractive for general purpose scientific computing. In this paper we show how graphics processors can be used for N-body... more
Abstract: Commercial graphics processors (GPUs) have high compute capacity at very low cost, which makes them attractive for general purpose scientific computing. In this paper we show how graphics processors can be used for N-body simulations to obtain improvements in performance over current generation CPUs. We have developed a highly optimized algorithm for performing the O (N^ 2) force calculations that constitute the major part of stellar and molecular dynamics simulations.
In simulations, molecular dispersion interactions are frequently neglected beyond a cutoff of around 1 nm. In some cases, analytical corrections appropriate for isotropic systems are applied to the pressure and/or the potential energy.... more
In simulations, molecular dispersion interactions are frequently neglected beyond a cutoff of around 1 nm. In some cases, analytical corrections appropriate for isotropic systems are applied to the pressure and/or the potential energy. Here, we show that in systems containing macromolecules, either of these approaches introduce statistically significant errors in some observed properties; for example, the choice of cutoff can affect computed free energies of ligand binding to proteins by 1 to 2 kcal/mol.
Abstract Recently, the importance of proline ring pucker conformations in collagen has been suggested in the context of hydroxylation of prolines. The previous molecular mechanics parameters for hydroxyproline, however, do not reproduce... more
Abstract Recently, the importance of proline ring pucker conformations in collagen has been suggested in the context of hydroxylation of prolines. The previous molecular mechanics parameters for hydroxyproline, however, do not reproduce the correct pucker preference. We have developed a new set of parameters that reproduces the correct pucker preference.
Abstract Markov state models (MSMs) are a powerful tool for modeling both the thermodynamics and kinetics of molecular systems. In addition, they provide a rigorous means to combine information from multiple sources into a single model... more
Abstract Markov state models (MSMs) are a powerful tool for modeling both the thermodynamics and kinetics of molecular systems. In addition, they provide a rigorous means to combine information from multiple sources into a single model and to direct future simulations/experiments to minimize uncertainties in the model.
Abstract Modern graphics processing units (GPUs) are flexibly programmable and have peak computational throughput significantly faster than conventional CPUs. Herein, we describe the design and implementation of PAPER, an open-source... more
Abstract Modern graphics processing units (GPUs) are flexibly programmable and have peak computational throughput significantly faster than conventional CPUs. Herein, we describe the design and implementation of PAPER, an open-source implementation of Gaussian molecular shape overlay for NVIDIA GPUs.
Markov state models provide a framework for understanding the fundamental states and rates in the conformational dynamics of biomolecules. We describe an improved protocol for constructing Markov state models from molecular dynamics... more
Markov state models provide a framework for understanding the fundamental states and rates in the conformational dynamics of biomolecules. We describe an improved protocol for constructing Markov state models from molecular dynamics simulations. The new protocol includes advances in clustering, data preparation, and model estimation; these improvements lead to significant increases in model accuracy, as assessed by the ability to recapitulate equilibrium and kinetic properties of reference systems.
Markovian state models (MSMs) are a convenient and efficient means to compactly describe the kinetics of a molecular system as well as a formalism for using many short simulations to predict long time scale behavior. Building a MSM... more
Markovian state models (MSMs) are a convenient and efficient means to compactly describe the kinetics of a molecular system as well as a formalism for using many short simulations to predict long time scale behavior. Building a MSM consists of grouping the conformations into states and estimating the transition probabilities between these states. In a previous paper, we described an efficient method for calculating the uncertainty due to finite sampling in the mean first passage time between two states.
Abstract Simulating the conformational dynamics of biomolecules is extremely difficult due to the rugged nature of their free energy landscapes and multiple long-lived, or metastable, states. Generalized ensemble (GE) algorithms, which... more
Abstract Simulating the conformational dynamics of biomolecules is extremely difficult due to the rugged nature of their free energy landscapes and multiple long-lived, or metastable, states. Generalized ensemble (GE) algorithms, which have become popular in recent years, attempt to facilitate crossing between states at low temperatures by inducing a random walk in temperature space. Enthalpic barriers may be crossed more easily at high temperatures; however, entropic barriers will become more significant.