Extension of the free energy workflow FEW towards implicit solvent/implicit membrane MM-PBSA calculations.

BACKGROUND The number of high-resolution structures of pharmacologically relevant membrane proteins has been strongly increasing. This makes computing relative affinities of chemically similar compounds binding to a membrane protein possible in order to guide decision making in drug design. However, the preparation step of such calculations is time-consuming and complex. METHODS We extended the free energy workflow tool FEW, available in AMBER, towards facilitating the setup of molecular dynamics simulations with explicit membrane, and the setup and execution of effective binding energy calculations according to a 1-trajectory implicit solvent/implicit membrane MM-PBSA approach for multiple ligands binding to the same membrane protein. RESULTS We validated the implemented protocol initially on two model systems, a sodium ion in the presence of an implicit membrane slab and a proton traversing the M2 proton-channel of the influenza A virus. For the latter, we found a good agreement for several important events along the proton pathway with those obtained in a recent computational study. Finally, we performed a case study on effective binding energy calculations for a set of inhibitors binding to the M2 proton-channel. CONCLUSIONS From the case study, we estimate a considerable speed up in the setup and analysis times for implicit solvent/implicit membrane MM-PBSA calculations by the extended version of FEW compared to a manual preparation. GENERAL SIGNIFICANCE Together with the overall runtime and the analysis results, this suggests that such type of calculations can be valuable in later stages of drug design projects on membrane proteins. This article is part of a Special Issue entitled Recent developments of molecular dynamics.