OpenMM 7: Rapid Development of High Performance Algorithms for Molecular Dynamics

Eastman, Peter; Swails, Jason M.; Chodera, John D.; McGibbon, Robert T.; Zhao, Yulan; Beauchamp, Kyle A.; Wang, Lee‐Ping; Simmonett, Andrew C.; Harrigan, Matthew P.; Stern, Chaya; Wiewiora, Rafal; Brooks, Bernard R.; Pande, Vijay S.

doi:10.1101/091801

Cited by 318 publications

(421 citation statements)

References 37 publications

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“…Simulations for parameterization. All the MD simulations for the ion model parameterization were performed with OpenMM (version 7.0.1) 44 , as the package is highly flexible and can be easily customized with a Python interface, and the CHARMM force field 45 (version C36_Aug15) was utilized in this work.…”

Section: Methodsmentioning

confidence: 99%

The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Zhang

Liu

et al. 2020

Nat Commun

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Ryanodine receptors (RyR) are ion channels responsible for the release of Ca 2+ from the sarco/endoplasmic reticulum and play a crucial role in the precise control of Ca 2+ concentration in the cytosol. The detailed permeation mechanism of Ca 2+ through RyR is still elusive. By using molecular dynamics simulations with a specially designed Ca 2+ model, we show that multiple Ca 2+ ions accumulate in the upper selectivity filter of RyR1, but only one Ca 2+ can occupy and translocate in the narrow pore at a time, assisted by electrostatic repulsion from the Ca 2+ within the upper selectivity filter. The Ca 2+ is nearly fully hydrated with the first solvation shell intact during the whole permeation process. These results suggest a remote knock-on permeation mechanism and one-at-a-time occupation pattern for the hydrated Ca 2+ within the narrow pore, uncovering the basis underlying the high permeability and low selectivity of the RyR channels.

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Section: Methodsmentioning

confidence: 99%

The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Zhang

Liu

et al. 2020

Nat Commun

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“…Equilibration and production MD simulation details. The MD simulations were performed using OpenMM 7.1.1 35 . We used a Langevin integrator with 2 fs time step and a friction coefficient of 1 ps −1 .…”

Section: Methodsmentioning

confidence: 99%

Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics

Sasmal

Gill

Lim

et al. 2020

J. Chem. Theory Comput.

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Flexible ligands often have multiple binding modes or bound conformations that differ by rotation of a portion of the molecule around internal rotatable bonds. Knowledge of these binding modes is important for understanding the interactions stabilizing the ligand in the binding pocket, and also for calculating accurate binding affinities. In this work, we use a hybrid molecular dynamics (MD)/nonequilibrium candidate Monte Carlo (NCMC) method to sample the different binding modes of several flexible ligands and also to estimate the population distribution of the modes. The NCMC move proposal is divided into three parts. The flexible part of the ligand is alchemically turned off by decreasing the electrostatics and steric interactions gradually, followed by rotating the rotatable bond by a random angle and then slowly turning the ligand back on to its fully interacting state. The alchemical steps prior to and after the move proposal help the surrounding protein and water atoms in the binding pocket relax around the proposed ligand conformation and increase move acceptance rates. The protein-ligand system is propagated using classical MD in between the NCMC proposals. Using this MD/NCMC method, we were able to correctly reproduce the different binding modes of inhibitors binding to two kinase targets -c-Jun N-terminal kinase-1 and cyclin-dependent kinase 2 -at a much lower computational cost compared to conventional MD and umbrella sampling. This method is available as a part of the BLUES software package.

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“…The system was parameterized using tleap in AmberTools18 63 by ff14SB 64 and LIPID17 force elds, and along with TIP3P water model 65 . All the simulations were performed using OpenMM7 66 . We rst applied positional constraints (k=10 kcal/mol/Å 2 ) on protein heavy atoms for a 5000-step minimization, then released constraints of side-chains when heating up the system to 310 K with 2 fs stepsize (H-bonds constraints), 1 ps-1 friction coe cient for Langevin dynamics, Particle Mesh Ewald (PME) method 67 , and 12 Å non-bonded cutoff.…”

Section: Molecular Dynamics Simulationmentioning

confidence: 99%

Structure of human sodium leak channel NALCN in complex with FAM155A

Xie

Meng

et al. 2020

Preprint

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NALCN, a sodium leak channel mainly expressed in the central nervous systems, is responsible for the resting Na+ permeability that controls neuronal excitability. Dysfunctions of the NALCN channelosome, NALCN with several auxiliary subunits, are associated with a variety of human diseases. Here, we reported the cryo-EM structure of human NALCN in complex with FAM155A, at an overall resolution of 3.1 angstrom. FAM155A forms extensive interactions with the extracellular loops of NALCN that help stabilize NALCN in the membrane. A Na+ ion-binding site, reminiscent of a Ca2+ binding site in Cav channels, is identified in the unique EEKE selectivity filter. Despite its ‘leaky’ nature, the intracellular gate is sealed by S6I, II-III linker and III-IV linker. Our study establishes the molecular basis of Na+ permeation and voltage sensitivity, and provides important clues to the mechanistic understanding of NALCN regulation and NALCN channelosome-related diseases.

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OpenMM 7: Rapid Development of High Performance Algorithms for Molecular Dynamics

Cited by 318 publications

References 37 publications

The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

The Ca2+ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Sampling Conformational Changes of Bound Ligands Using Nonequilibrium Candidate Monte Carlo and Molecular Dynamics

Structure of human sodium leak channel NALCN in complex with FAM155A

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