MoMA-LigPath: a web server to simulate protein-ligand unbinding

Abstract

Protein-ligand interactions taking place far away from the active site, during ligand binding or release, may determine molecular specificity and activity. However, obtaining information about these interactions with experimental or computational methods remains difficult. The computational tool presented in this article, MoMA-LigPath, is based on a mechanistic representation of the molecular system, considering partial flexibility, and on the application of a robotics-inspired algorithm to explore the conformational space. Such a purely geometric approach, together with the efficiency of the exploration algorithm, enables the simulation of ligand unbinding within short computing time. Ligand unbinding pathways generated by MoMA-LigPath are a first approximation that can provide useful information about protein-ligand interactions. When needed, this approximation can be subsequently refined and analyzed using state-of-the-art energy models and molecular modeling methods. MoMA-LigPath is available at http://moma.laas.fr. The web server is free and open to all users, with no login requirement.

Figure 1.

Structure of the R₆ hexameric insulin–phenol complex. The phenol molecule in the pocket between chains A, B, F and H can follow different unbinding pathways. The two most likely pathways are located at the interface of chains A, F and H. However, diffusion through the inner part of the hexamer is also geometrically feasible. Images of molecular models in this article have been generated using PyMOL (19).

Figure 2.

Different paths for phenol unbinding from the R₆ insulin hexamer obtained by MoMA-LigPath. The location of the phenol molecule and the conformations of moving side-chains are represented for some intermediate frames. The two images at the top correspond to paths following the most likely unbinding pathways: PW1 and PW2. The image at the bottom illustrates one of the pathways going through the inner part of the insulin hexamer.