Identification of GPCR Transition Pathways using Go Models

Abstract

One caveat of standard all-atom molecular dynamics (MD) simulations is that they are resource-intensive, particularly when inspecting state transition pathways. To date, the timescales involved in processes such as G protein-coupled receptor (GPCR) activation make it largely impossible to study them using standard all-atom MD under equilibrium conditions. Indeed, the nature of their activation/deactivation pathway(s) is not yet fully characterized. To overcome this issue, our group previously showed that simpler structure-based (Go-like) potentials could be used to study GPCR state transitions, yielding results in qualitative agreement with those obtained from standard all-atom simulations but with negligible computational cost. These potentials are energetically smooth by design with few non-native traps and a single global energy minimum corresponding to the end-point of the transition of interest. In the case of rhodopsin, a prototypical GPCR, two distinct but reproducible pathways were observed to be populated during activation and deactivation. While it is possible that a separation of pathways is mechanistically required for function, it could also be the result of simulating state transitions occurring in two separate energy surfaces out of equilibrium (one for activation and one for deactivation). To address this potential source of error, we implemented a strategy for modeling Go-like energy landscapes with multiple energy minima at all-heavy atom resolution. This approach allows the study of state interconversion in equilibrium and extensive sampling, still at a low computational cost. Moreover, it can also be used for quick hypothesis testing, to characterize the effects of different ligands, model point mutations, study substate fluctuations and guide all-atom simulations by quickly generating reasonable reaction coordinates. As long as the end states are known, this strategy can be extrapolated to almost any biomolecular system in a straight forward manner, complementing current standard all-atom MD approaches.