Abstract
Central among the tools and approaches used for ligand discovery and design are Molecular Dynamics (MD) simulations, which follow the dynamic changes in molecular structure in response to the environmental condition, interactions with other proteins, and the effects of ligand binding. The need for, and successes of, MD simulations in providing this type of essential information are well documented, but so are the challenges presented by the size of the resulting datasets encoding the desired information. The difficulty of extracting information on mechanistically important state-to-state transitions in response to ligand binding and other interactions is compounded by these being rare events in the MD trajectories of complex molecular machines, such as G-protein-coupled receptors (GPCRs). To address this problem, we have developed a protocol for the efficient detection of such events. We show that the novel Rare Event Detection (RED) protocol reveals functionally relevant and pharmacologically discriminating responses to the binding of different ligands to the 5-HT2AR orthosteric site in terms of clearly defined, structurally coherent, and temporally ordered conformational transitions. This information from the RED protocol offers new insights into specific ligand-determined functional mechanisms encoded in the MD trajectories, which opens a new and rigorously reproducible path to understanding drug activity with application in drug discovery.
Highlights
The detection of structural changes occurring in the course of Molecular Dynamics (MD) trajectories of macromolecular systems such as the G-protein-coupled receptors (GPCRs) is a main step in the analysis of the relationship between structure and dynamics in their functional mechanisms [1,2,3,4]
We have demonstrated the collective nature of these conformational transitions in studies of ligand-dependent functional selectivity of the 5-HT2A serotonin receptor (5-HT2AR) and the dopamine D2 receptor, and have shown that understanding such ligand-determined GPCR functions depends on a rigorous identification and analysis of the diverse function-related conformational transitions induced by various ligands
With the Rare Events Detection (RED) protocol, we have been able to identify in MD trajectory data the set of function-related rare events that lead to the known pharmacological responses of different ligands, such as the diametrically opposed activation/deactivation responses of the 5-HT2AR to the agonist serotonin (5-HT) and the inverse agonist Ketanserin (KET) when each is bound to the orthosteric site
Summary
The detection of structural changes occurring in the course of Molecular Dynamics (MD) trajectories of macromolecular systems such as the G-protein-coupled receptors (GPCRs) is a main step in the analysis of the relationship between structure and dynamics in their functional mechanisms [1,2,3,4]. Given the massive amount of information collected in the MD simulation trajectories employed in current methods of drug discovery and design, this task is made difficult by the presence of data in these simulation trajectories, from a very large number of fluctuation events that do not represent collective motions and do not result in conformational transitions. Rather, they represent the sampling of disparate degrees of freedom of the protein that can occur individually on a similar scale to that of the collective ones. To enable an efficient identification of relevant conformational transition in GPCR trajectories and overcome the difficulties in the analysis of differences in functional mechanisms of GPCRs in complex with different ligands, we have developed a Rare Events Detection (RED) protocol based on a Machine Learning analysis of MD trajectories
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