Advanced Computational Methods in Protein Simulations: A Case Study of Enhanced Sampling Applied to Membrane...

We review the use of state-of-the-art enhanced sampling techniques in molecular dynamics (MD) simulations. We briefly introduce the principles and practical considerations underlying the application of these methods, making reference to recent reviews, and then discuss their application to membrane transporters as case studies. Our discussion is structured around the respective method employed and the biological problem case in question. We categorise the latter on a conceptual basis primarily into 'conformational change' problems which encompass alternating access and other related intra-protein motions and inter-molecular 'interactions' problems, which relate to ligands, proteins or allosteric modulators. Lastly, we consider future developments that we anticipate in this field, including the increasing prominence of machine learning techniques used in combination with MD, and make some recommendations with regard to standardised reporting to improve reproducibility and transferability.