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

Abstract

Molecular dynamics (MD) simulations have been used extensively to study P-glycoprotein (P-gp), a flexible multidrug transporter that is a key player in the development of multidrug resistance to chemotherapeutics. A substantial body of literature has grown from simulation studies that have employed various simulation conditions and parameters, including AMBER, CHARMM, OPLS, GROMOS, and coarsegrained force fields, drawing conclusions from simulations spanning hundreds of nanoseconds. Each force field is typically parametrized and validated on different data and observables, usually of small molecules and peptides; there have been few comparisons of force field performance on large protein− membrane systems. Here we compare the conformational ensembles of P-gp embedded in a POPC/cholesterol bilayer generated over 500 ns of replicate simulation with five force fields from popular biomolecular families: AMBER 99SB-ILDN, CHARMM 36, OPLS-AA/L, GROMOS 54A7, and MARTINI. We find considerable differences among the ensembles with little conformational overlap, although they correspond to similar extents to structural data obtained from electron paramagnetic resonance and crosslinking studies. Moreover, each trajectory was still sampling new conformations at a high rate after 500 ns of simulation, suggesting the need for more sampling. This work highlights the need to consider known limitations of the force field used (e.g., biases toward certain secondary structures) and the simulation itself (e.g., whether sufficient sampling has been achieved) when interpreting accumulated results of simulation studies of P-gp and other transport proteins.

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

“…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.…”

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

“…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 ).…”

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

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