Enhanced Free Energy Sampling of Transmembrane Permeation

Justin Lee, Lianqing Zheng, Wei Yang

Florida State University

Prediction of transmembrane permeability has long been a topic of importance to biophysical understanding and novel drug discovery. Particularly all-atom molecular dynamics has a remarkable outlook in its viability to deliver chemical accuracy and ascertain mechanistic details under precise conditions. Recent literature shows that many simulations encounter obstacles in its ability to handle vigorously demanding free energy sampling of even seemingly simple molecular permeation processes. As is known, sampling difficulty arises from permeation-coupled slow environmental reorganizations or slow “hidden” events. Despite the fact some of these hidden events can be individually identifiable, there lacks a general effective strategy to derive transferable collective variables for robust sampling treatment. To tackle this issue, our novel sampling method development is focused on the employment of a unique physics-based technique to enable robust activation of slow hidden events.