Protein–protein binding pathways and calculations of rate constants using fully-continuous, explicit-solvent simulations

Saglam, Ali S.; Chong, Lillian T.

doi:10.1039/c8sc04811h

Cited by 89 publications

(107 citation statements)

References 56 publications

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“…XSEDE's Bridges) or 16 GPUs (e.g. NVIDIA Tesla P100 GPUs) proteinprotein association [10] barnase/barstar proteins in explicit solvent: >100,000 atoms 2D progress coordinate: (i) heavyatom RMSD of barstar residues D35 and D39 after alignment on barnase, and (ii) minimum protein-protein separation distance. D35 and D39 are the barstar residues that become the most buried upon binding barnase.…”

Section: Workflow Of Running a We Simulationmentioning

confidence: 99%

“…If you have only one structure, this file will contain the name of that structure only; if you have more than one structure, bstate.file should list each structure along with its associated statistical weight. An example of the latter is a representative ensemble of unbound protein conformations in a binding process that could be generated using a prior equilibrium WE simulation [9,10].…”

Section: Rare-event Processmentioning

confidence: 99%

“…The WESTPA software also includes plugins for using a WE-based string method [6] and a WE strategy utilizing hierarchical Voronoi bins (WExplore) [7]. The WESTPA software package has enabled efficient atomistic simulations of host-guest associations [8], protein binding processes [9,10], and protein folding [11]. This efficiency (relative to standard "brute force" simulations) has been demonstrated to increase exponentially with the effective free energy barrier of the rare event [12].…”

Section: Introduction and Scope Of Tutorialsmentioning

confidence: 99%

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A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0]

et al. 2019

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The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present five tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. Users are expected to already have significant experience with running standard molecular dynamics simulations using the underlying dynamics engine of interest (e.g. Amber, Gromacs, OpenMM). The tutorials range from a molecular association process in explicit solvent to more complex processes such as host-guest association, peptide conformational sampling, and protein folding.

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Section: Workflow Of Running a We Simulationmentioning

confidence: 99%

Section: Rare-event Processmentioning

confidence: 99%

Section: Introduction and Scope Of Tutorialsmentioning

confidence: 99%

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A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0]

et al. 2019

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“…This study shows that hypersound-stimulated MD simulations have the potential to accelerate protein-ligand binding processes through a solvent-mediated mechanism without collapse of the protein structure, thus enabling the atomic-scale observation of these processes within time scales accessible by standard MD (~ 100 ns). In contrast to other accelerated MD approaches (23,24), this method does not require prior knowledge of the protein-ligand complex structure. In this way, the simulations can provide significant insights into fundamental biological mechanisms (such as the discovery of microscopic ligand binding pathways involving various bound conformations) and facilitate drug discovery (as illustrated by the present exploration of druggable binding sites on the protein surface).…”

Section: Main Textmentioning

confidence: 99%

Exploring ligand binding pathways on proteins using hypersound–accelerated molecular dynamics

Araki

Matsumoto

Bekker

et al. 2020

Preprint

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Capturing the dynamic processes of biomolecular systems in atomistic detail remains difficult despite recent experimental advances. Although molecular dynamics (MD) techniques enable atomic-level observations, simulations of "slow" biomolecular processes (with timescales longer than submilliseconds) are challenging, due to current computer speed limitations. Therefore, we developed a new method to accelerate MD simulations by high-frequency ultrasound perturbation. The binding events between the protein CDK2 and its small-molecule inhibitors were nearly undetectable in 100-ns conventional MD, but the new method successfully accelerated their slow binding rates by up to 10-20 times. The accelerated MD simulations revealed a variety of microscopic kinetic features of the inhibitors on the protein surface, such as the existence of different binding pathways to the active site. Moreover, the simulations allowed estimating the corresponding kinetic parameters and exploring other druggable pockets. This method can thus provide deeper insight into the microscopic interactions controlling biomolecular processes. (149 /150 words)

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“…Using coarse-grained models of proteins, Monte Carlo simulations 24,27 and Brownian dynamics simulations 28 have been used to successfully characterize bound ensembles or equilibrium dissociation constants. Atomistic MD simulations of protein-protein association have been recently applied to measure binding kinetics 29,30 and binding free energies of the barnase-barstar interaction 29,31 , and binding pathways of four additional structured pairs 31 . Here we perform MD simulations with the coarse-grained MARTINI force field 32 , which was recently used to study binding free energies of transmembrane helix dimerization 33 .…”

Section: Introductionmentioning

confidence: 99%

Thermodynamics and free energy landscape of BAR-domain dimerization from molecular simulations

Jhaveri

Maisuria

Varga

et al. 2020

Preprint

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Nearly all proteins interact specifically with other proteins, often forming reversible bound structures whose stability is critical to function. Proteins with BAR domains function to bind to, bend, and remodel biological membranes, where the dimerization of BAR domains is a key step in this function. Here we characterize the binding thermodynamics of homodimerization between the LSP1 BAR domain proteins in solution, using Molecular Dynamics (MD) simulations. By combining the MARTINI coarse-grained protein models with enhanced sampling through metadynamics, we construct a two-dimensional free energy surface quantifying the bound versus unbound ensembles as a function of two distance variables. Our simulations portray a heterogeneous and extraordinarily stable bound ensemble for these modeled LSP1 proteins. The proper crystal structure dimer has a large hydrophobic interface that is part of a stable minima on the free energy surface, which is enthalpically the minima of all bound structures. However, we also find several other stable nonspecific dimers with comparable free energies to the specific dimer. Through structure-based clustering of these bound structures, we find that some of these ‘nonspecific’ contacts involve extended tail regions that help stabilize the higher-order oligomers formed by BAR-domains, contacts that are separated from the homodimer interface. We find that the known membrane-binding residues of the LSP1 proteins rarely participate in any of the bound interfaces, but that both patches of residues are aligned to interact with the membrane in the specific dimer. Hence, we would expect a strong selection of the specific dimer in binding to the membrane. The effect of a 100mM NaCl buffer reduces the relative stability of nonspecific dimers compared to the specific dimer, indicating that it would help prevent aggregation of the proteins. With these results, we provide the first free energy characterization of interaction pathways in this important class of membrane sculpting domains, revealing a variety of interfacial contacts outside of the specific dimer that may help stabilize its oligomeric assemblies.

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Protein–protein binding pathways and calculations of rate constants using fully-continuous, explicit-solvent simulations

Abstract: The weighted ensemble (WE) strategy enables direct simulation of atomistic, fully-continuous protein–protein binding pathways in explicit solvent, yielding rigorous kinetics.

Cited by 89 publications

References 56 publications

A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0]

A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0]

Exploring ligand binding pathways on proteins using hypersound–accelerated molecular dynamics

Thermodynamics and free energy landscape of BAR-domain dimerization from molecular simulations

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