Hidden GPCR structural transitions addressed by multiple walker supervised molecular dynamics (mwSuMD)

G protein-coupled receptors (GPCRs) are the most abundant membrane proteins and the target of about 35% of approved drugs, but the structural basis of GPCR pharmacology is still a matter of intense study. Here, we present an unbiased molecular dynamics adaptive sampling algorithm, namely multiple walker supervised molecular dynamics (mwSuMD), that performs well on different hidden transitions involving GPCRs. Molecular dynamics (MD) simulations aim at expanding the knowledge of GPCR dynamics by building upon the recent advances in structural biology. However, the timescale limitations of classic MD hinder its applicability to numerous structural processes happening in time scales longer than microseconds (hidden structural transitions), limiting the overall MD impact on the study of GPCRs, hence our new algorithm. By increasing the complexity of the simulated process, we report the binding and unbinding of the vasopressin peptide from its receptor V2, the inactive-to-active transition of the glucagon-like peptide-1 receptor (GLP-1R), and the stimulatory (Gs) and inhibitory (Gi) G proteins binding to the adrenoreceptor β2 (β2 AR) and the adenosine 1 receptor (A1R), respectively. Finally, we report on the heterodimerization between the adenosine receptor A2 (A2AR) and the dopamine receptor D2 (D2R). We demonstrate mwSuMD usefulness for studying atomic-level GPCR transitions that are challenging to address with classic MD simulations.

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