Gramicidin A Channel as a Test Ground for Molecular Dynamics Force Fields

• Published in: Biophysical journal Vol. 84; no. 4; pp. 2159 - 2168
• Main Authors: Allen, Toby W., Baştuğ, Turgut, Kuyucak, Serdar, Chung, Shin-Ho
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2003; Biophysical Society
• Subjects: Binding Sites; Biophysical Theory and Modeling; Cell Membrane Permeability; Computer Simulation; Crystallography - methods; Dimerization; Dimyristoylphosphatidylcholine - chemistry; Gramicidin - chemistry; Ion Channel Gating; Ion Channels - chemistry; Ions; Lipid Bilayers - chemistry; Macromolecular Substances; Models, Molecular; Molecular Conformation; Molecules; Motion; Neurotransmitters; Quality Control; Reproducibility of Results; Sensitivity and Specificity; Static Electricity; Stress, Mechanical
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(03)75022-X

We use the well-known structural and functional properties of the gramicidin A channel to test the appropriateness of force fields commonly used in molecular dynamics (MD) simulations of ion channels. For this purpose, the high-resolution structure of the gramicidin A dimer is embedded in a dimyristoylphosphatidylcholine bilayer, and the potential of mean force of a K + ion is calculated along the channel axis using the umbrella sampling method. Calculations are performed using two of the most common force fields in MD simulations: CHARMM and GROMACS. Both force fields lead to large central barriers for K + ion permeation, that are substantially higher than those deduced from the physiological data by inverse methods. In long MD simulations lasting over 60 ns, several ions are observed to enter the binding site but none of them crossed the channel despite the presence of a large driving field. The present results, taken together with many earlier studies, highlights the shortcomings of the standard force fields used in MD simulations of ion channels and calls for construction of more appropriate force fields for this purpose.