Fast Implementation of the Nudged Elastic Band Method in AMBER

Ghoreishi, Delaram; Cerutti, David S.; Fallon, Zachary; Simmerling, Carlos; Roitberg, Adrián E.

doi:10.1021/acs.jctc.9b00329

Cited by 15 publications

(16 citation statements)

References 46 publications

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“…A short targeted MD run was used to connect the equilibrated end states. From the targeted MD trajectory we selected 32 evenly spaced snapshots (replicas) that served to initiate our path optimization protocol, employing the partial nudged elastic band method (PNEB) 25 , 26 . In PNEB, the minimum energy path connecting protein functional states is represented by a series of replicas of the simulation system.…”

Section: Resultsmentioning

confidence: 99%

“…The exo-mode conformation was selected as the TMD target and the pol-mode conformation was driven to the target with a force constant of 1000 kcal mol −1 Å −2 . From the TMD trajectory we selected 32 evenly spaced snapshots (replicas) at 312-ps intervals that served to initiate our path optimization protocol, employing the partial nudged elastic band method (PNEB) 25 , 26 . The optimization protocol was carried out in several stages.…”

Section: Methodsmentioning

confidence: 99%

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Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path

et al. 2020

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Proofreading by replicative DNA polymerases is a fundamental mechanism ensuring DNA replication fidelity. In proofreading, mis-incorporated nucleotides are excised through the 3′-5′ exonuclease activity of the DNA polymerase holoenzyme. The exonuclease site is distal from the polymerization site, imposing stringent structural and kinetic requirements for efficient primer strand transfer. Yet, the molecular mechanism of this transfer is not known. Here we employ molecular simulations using recent cryo-EM structures and biochemical analyses to delineate an optimal free energy path connecting the polymerization and exonuclease states of E. coli replicative DNA polymerase Pol III. We identify structures for all intermediates, in which the transitioning primer strand is stabilized by conserved Pol III residues along the fingers, thumb and exonuclease domains. We demonstrate switching kinetics on a tens of milliseconds timescale and unveil a complete pol-to-exo switching mechanism, validated by targeted mutational experiments.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path

et al. 2020

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“…The CHARMM27 all-atom force field [ 48 , 49 ], along with cMAP correction for backbone, particle mesh Ewald (PME) algorithm [ 50 ] for electrostatic interaction, a 12 Å cut off for electrostatic and van der Waals interaction, was used here to perform MD simulations with periodical boundary condition and time step of 2 fs. The system was minimized firstly at 5000 steps with heavy or non-hydrogen protein atoms being fixed, and then minimized at 5000 steps with all atoms free.…”

Section: Methodsmentioning

confidence: 99%

Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations

Feng

Zhang

et al. 2020

IJMS

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The PSGL-1-actin cytoskeleton linker proteins ezrin/radixin/moesin (ERM), an adaptor between P-selectin glycoprotein ligand-1 (PSGL-1) and spleen tyrosine kinase (Syk), is a key player in PSGL-1 signal, which mediates the adhesion and recruitment of leukocytes to the activated endothelial cells in flow. Binding of PSGL-1 to ERM initials intracellular signaling through inducing phosphorylation of Syk, but effects of tensile force on unligation and phosphorylation site exposure of ERM bound with PSGL-1 remains unclear. To answer this question, we performed a series of so-called “ramp-clamp” steered molecular dynamics (SMD) simulations on the radixin protein FERM domain of ERM bound with intracellular juxtamembrane PSGL-1 peptide. The results showed that, the rupture force of complex pulled with constant velocity was over 250 pN, which prevented the complex from breaking in front of pull-induced exposure of phosphorylation site on immunoreceptor tyrosine activation motif (ITAM)-like motif of ERM; the stretched complex structure under constant tensile forces <100 pN maintained on a stable quasi-equilibrium state, showing a high mechano-stabilization of the clamped complex; and, in consistent with the force-induced allostery at clamped stage, increasing tensile force (<50 pN) would decrease the complex dissociation probability but facilitate the phosphorylation site exposure, suggesting a force-enhanced biophysical connectivity of PSGL-1 signaling. These force-enhanced characters in both phosphorylation and unligation of ERM bound with PSGL-1 should be mediated by a catch-slip bond transition mechanism, in which four residue interactions on binding site were involved. This study might provide a novel insight into the transmembrane PSGL-1 signal, its biophysical connectivity and molecular structural basis for cellular immune responses in mechano-microenvironment, and showed a rational SMD-based computer strategy for predicting structure-function relation of protein under loads.

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“…We used a GPU implementation 86 of a large-system variant 53 of the nudged elastic band (NEB) method 87 to explore a pathway of the spike transition between the closed and 1-up RBD states. We previously used this protocol to obtain pathways for biomolecular recognition dynamics that were subsequently validated through experiments.…”

Section: Nudged Elastic Band Pathway Optimizationmentioning

confidence: 99%

Free Energy Landscapes for RBD Opening in SARS-CoV-2 Spike Glycoprotein Simulations Suggest Key Interactions and a Potentially Druggable Allosteric Pocket

Fallon¹,

Belfon²,

Raguette³

et al. 2020

Preprint

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The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) an enveloped, positive-sense single-stranded RNA virus that is responsible for the COVID-19 pandemic. The viral spike is a class I viral fusion glycoprotein that extends from the viral surface and is responsible for viral entry into the host cell, and is the primary target of neutralizing antibodies. However, antibody recognition often involves variable surface epitopes on the spike, and the receptor binding domain (RBD) of the spike hides from immune recognition underneath a glycan shield aside from brief dynamic excursions to search for the host-cell surface receptor ACE2. Using an atomistic model of the glycosylated wild-type spike in the closed and 1-up RBD conformations, we identified specific interactions that stabilize the closed RBD, and mapped the free energy landscape for RBD opening. We characterized a transient pocket associated with a hinge motion during opening of the RBD, suggesting the possibility of allosteric control of the RBD via this region. Substitution of a conserved alanine to bulkier leucine in the pocket shifted the RBD equilibrium to favor the open, exposed state, as did removal of a conserved lysine that forms a critical salt-bridge in the closed, hidden state. Results from our virtual screening, MD simulations and free energy landscape calculations for wild-type spike suggest that small molecules can spontaneously bind to the highly conserved hinge pocket, and that such binding can shift the RBD equilibrium to favor the open state. Stabilizing the open state may facilitate antibody recognition by forcing the spike to expose critical RBD epitopes, and also could increase the likelihood of premature triggering of the spike fusion machinery via S1 shedding, neutralizing the infectious ability of the virus.

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Fast Implementation of the Nudged Elastic Band Method in AMBER

Cited by 15 publications

References 46 publications

Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path

Polymerization and editing modes of a high-fidelity DNA polymerase are linked by a well-defined path

Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations

Free Energy Landscapes for RBD Opening in SARS-CoV-2 Spike Glycoprotein Simulations Suggest Key Interactions and a Potentially Druggable Allosteric Pocket

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