A Hybrid Approach to Structure and Function Modeling of G Protein-Coupled Receptors.

The recent GPCR Dock 2013 assessment of serotonin receptor 5-HT1B and 5-HT2B, and smoothened receptor SMO targets, exposed the strengths and weaknesses of the currently used computational approaches. The test cases of 5-HT1B and 5-HT2B demonstrated that both the receptor structure and the ligand binding mode can be predicted with the atomic-detail accuracy, as long as the target-template sequence similarity is relatively high. On the other hand, the observation of a low target-template sequence similarity, e.g., between SMO from the frizzled GPCR family and members of the rhodopsin family, hampers the GPCR structure prediction and ligand docking. Indeed, in GPCR Dock 2013, accurate prediction of the SMO target was still beyond the capabilities of most research groups. Another bottleneck in the current GPCR research, as demonstrated by the 5-HT2B target, is the reliable prediction of global conformational changes induced by activation of GPCRs. In this work, we report details of our protocol used during GPCR Dock 2013. Our structure prediction and ligand docking protocol was especially successful in the case of 5-HT1B and 5-HT2B-ergotamine complexes for which we provide one of the most accurate predictions. In addition to a description of the GPCR Dock 2013 results, we propose a novel hybrid computational methodology to improve GPCR structure and function prediction. This computational methodology employs two separate rankings for filtering GPCR models. The first ranking is ligand-based while the second is based on the scoring scheme of the recently published BCL method. In this work, we prove that the use of knowledge-based potentials implemented in BCL is an efficient way to cope with major bottlenecks in the GPCR structure prediction. Thereby, we also demonstrate that the knowledge-based potentials for membrane proteins were significantly improved, because of the recent surge in available experimental structures.