We extend the theory of hybrid explicit implicit solvent models to include an explicit domain tha... 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 coordina... 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 g... 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 parallelize... 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 viru... 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... 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 me... 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 c... 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... 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... 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 an... 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 femtoseco... 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-limiti... 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 throu... 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 h... 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 rece... 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 simu... 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 macromole... 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... 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 b... 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.
We extend the theory of hybrid explicit implicit solvent models to include an explicit domain tha... 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 coordina... 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 g... 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 parallelize... 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 viru... 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... 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 me... 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 c... 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... 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... 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 an... 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 femtoseco... 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-limiti... 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 throu... 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 h... 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 rece... 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 simu... 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 macromole... 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... 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 b... 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.
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Papers by Vijay Pande