Effect of the Force Field on Molecular Dynamics Simulations of the Multidrug Efflux Protein P-Glycoprotein

Wang, Lily; O’Mara, Megan L.

doi:10.1021/acs.jctc.1c00414

Cited by 28 publications

(21 citation statements)

References 148 publications

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“…The Chemistry at HARvard Macromolecular Mechanics (CHARMM)-36 was used as a governing force field. [35] [36] The position coordinates and velocity vectors of each atom and water molecule were calculated in each 2.0 femtosecond (10 -15 s). The cut-off length of 12 Å was set as the maximum distance allowing direct interactions of atoms as previously published.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

Nakayama

Goto

2022

TH Open

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Glycoprotein (GP: HIS1-PRO265) Ibα is a receptor protein expressed on the surface of the platelet. Its N-terminus domain binds with the A1 domain (ASP1269-PRO1472) of its ligand protein von Willebrand factor (VWF) and plays a unique role for platelet adhesion under blood flow conditions. Single amino acid substitutions at residue 233 from Glycine(G) to Alanine(A), Aspartic acid(D), or Valine(V) are known to cause bio-chemically distinct functional alterations known as equal, loss, and gain of function, respectively. However, the underlying physical characteristics of VWF binding with GPIbα in wild type and the three mutants exerting different biological functions are unclear. Here, we aimed to test the hypothesis: biological characteristics of macromolecules is influenced by small changes in physical parameters. The position coordinates and velocity vectors of all atoms and water molecules constructing the wild type and the three mutants of GPIbα (G233A, G233D, and G233V) bound with VWF were calculated every 2 x 10-15 sec using the CHARMM (Chemistry at HARvard Macromolecular Mechanics) force field for 9 x 10-10 sec. Six salt bridges were detected for longer than 50% of the calculation period for the wild-type model generating a non-covalent binding energy of -1096±137.6 kcal/mol. In contrast, only 4 pairs of salt bridges were observed in G233D mutant with a non-covalent binding energy of -865±139. For G233A and G233V, there were 6 and 5 pairs of salt bridges generating -929.8±88.5 and -989.9±94.0 kcal/mol of non-covalent binding energy, respectively. Our molecular dynamic simulation showing lower probability of salt bridge formation with less non-covalent binding energy between VWF binding with the biologically loss of function G233D mutant of GPIbα as compared to wild-type, equal function, and gain of function mutant suggest that biological functions of macromolecules such as GPIbα are influenced by their small changes in physical characteristics.

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Section: Accepted Manuscriptmentioning

confidence: 99%

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

Nakayama

Goto

2022

TH Open

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“…The approximation and parameterization of atomic-level forces are the main limitations of the different force fields, which may further lead to variations in the ensemble generated by the simulation ( Wang and O'Mara, 2021 ). In the current study, different force field effects have not been investigated on the studied systems, but only a well-known force field for protein and small molecules, i.e., OPLS3e, has been used throughout the study ( Roos et al., 2019 ) ( Dhanjal et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study

Malik

Kumar

Kaul

et al. 2021

Current Research in Structural Biology

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Serine/threonine-protein kinase B-raf (BRAF) plays a significant role in regulating cell division and proliferation through MAPK/ERK pathway. The constitutive expression of wild-type BRAF (BRAF WT ) and its mutant forms, especially V600E (BRAF V600E ), has been linked to multiple cancers. Various synthetic drugs have been approved and are in clinical trials, but most of them are reported to become ineffective within a short duration. Therefore, combinational therapy involving multiple drugs are often recruited for cancer treatment. However, they lead to toxicity and adverse side effects. In this computational study, we have investigated three natural compounds, namely Withaferin-A (Wi-A), Withanone (Wi-N) and Caffeic Acid Phenethyl ester (CAPE) for anti-BRAF WT and anti-BRAF V600E activity. We found that these compounds could bind stably at ATP-binding site in both BRAF WT and BRAF V600E proteins. In-depth analysis revealed that these compounds maintained the active conformation of wild-type BRAF protein by inducing αC-helix-In, DFG-In, extended activation segment and well-aligned R-spine residues similar to already known drugs Vemurafenib (VEM), BGB283 and Ponatinib. In terms of binding energy, among the natural compounds, CAPE showed better affinity towards both wild-type and V600E mutant proteins than the other two compounds. These data suggested that CAPE, Wi-A and Wi-N have potential to block constitutive autophosphorylation of BRAF and hence warrant in vitro and in vivo experimental validation.

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“…50,51 The approach applied in this work classifies RNA dynamics into Tier-0 (distinct secondary structure dynamics, > 0.1 s), Tier-1 (base-pair and tertiary dynamics, ms to s), and Tier-2 (thermodynamic jittering of bases and base stacking, ps to µs) which was introduced by Mustoe et al based on the original hierarchical descriptions of functionally important protein dynamics developed by Frauenfelder et al 50,51 Molecular dynamics simulations. Accurate description of structure and dynamics expected for biological function, in terms of hierarchical RNA dynamics tiers, requires computational techniques involving an experimentally relevant starting structure, 41-44 a forcefield attuned to the system, 52,53 and a timescale that can access the functionally important conformational changes. [47][48][49] Overall, three s2m systems were modeled and simulated in this study: SARS-CoV s2m based on 1XJR coordinates, SARS-CoV-2 s2m homology model based on 1XJR coordinates, and SARS-CoV-2 s2m leveraging NMR NOE assignments 38 and knowledge-based RNAComposer 45 coordinates.…”

Section: Methodsmentioning

confidence: 99%

Structural, Dynamical, and Entropic Differences Between SARS-CoV and SARS-CoV-2 s2m Elements Using Molecular Dynamics Simulations

Kensinger

Makowski

Pellegrene

et al. 2022

Preprint

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The functional role of the highly conserved stem-loop II motif (s2m) in SARS-CoV and SARS-CoV-2 in the viral lifecycle remains enigmatic and an intense area of research. Structure and dynamics of the s2m are key to establishing a structure-function connection, yet a full set of atomistic resolution coordinates is not available for SARS-CoV-2 s2m. Our work constructs three-dimensional coordinates consistent with NMR solution phase data for SARS-CoV-2 s2m and provides a comparative analysis with its counterpart SARS-CoV s2m. We employed initial coordinates based on PDB ID: 1XJR for SARS-CoV s2m and two models for SARS-CoV-2 s2m: one based on 1XJR in which we introduced the mutations present in SARS-CoV-2 s2m and the second based on the available SARS-CoV-2 NMR NOE data supplemented with knowledge-based methods. For each of the three systems, 3500 ns molecular dynamics simulations were used to sample the structure and dynamics, and principal component analysis (PCA) reduced the ensembles to hierarchal conformational substates for detailed analysis. Dilute solution simulations of SARS-CoV s2m, demonstrate that the GNRA-like terminal pentaloop is rigidly defined by base stacking uniquely positioned for possible kissing dimer formation. However, the SARS-CoV-2 s2m simulation did not retain the reported crystallographic SARS-CoV motifs and the terminal loop expands to a highly dynamic “nonaloop.” Increased flexibility and structural disorganization are observed for the larger terminal loops, where an entropic penalty is computed to explain the experimentally observed reduction in kissing complex formation. Overall, both SARS-CoV and SARS-CoV-2 s2m elements have a similarly pronounced L-shape due to different motif interactions. Our study establishes the atomistic three-dimensional structure and uncovers dynamic differences that arise from s2m sequence changes, which sets the stage for the interrogation of different mechanistic pathways of suspected biological function.

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Effect of the Force Field on Molecular Dynamics Simulations of the Multidrug Efflux Protein P-Glycoprotein

Cited by 28 publications

References 148 publications

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

Physical Characteristics of von Willebrand Factor Binding with Platelet Glycoprotein Ibɑ Mutants at Residue 233 Causing Various Biological Functions

Potential of Withaferin-A, Withanone and Caffeic Acid Phenethyl ester as ATP-competitive inhibitors of BRAF: A bioinformatics study

Structural, Dynamical, and Entropic Differences Between SARS-CoV and SARS-CoV-2 s2m Elements Using Molecular Dynamics Simulations

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