Investigation of the free energy profiles of amantadine and rimantadine in the AM2 binding pocket.

The purpose of this work was to study the mechanism of drug resistance of M2 channel proteins by analyzing the interactions between the drugs amantadine and rimantadine and M2 channel proteins (including the wild type and the three mutants V27A, S31N, and G34A) and the drug binding pathways, by use of a computational approach. Our results showed that multiple drug-binding sites were present in the M2 channel, and the trajectory of the drugs through the M2 channel was determined. A novel method was developed to investigate of free energy profiles of the ligand-protein complexes. Our work provides a new explanation of the large amount of experimental data on drug efficacy.