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Biomolecular Systems
Open Boundary-Molecular Mechanics/CoarseGrained Framework for Simulations of Low-Resolution G-Protein-Coupled Receptor/Ligand Complexes Thomas Tarenzi, Vania Calandrini, Raffaello Potestio, and Paolo Carloni J. Chem. Theory Comput., Just Accepted Manuscript • DOI: 10.1021/acs.jctc.9b00040 • Publication Date (Web): 14 Feb 2019 Downloaded from http://pubs.acs.org on February 15, 2019
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Journal of Chemical Theory and Computation
Open Boundary-Molecular Mechanics/CoarseGrained Framework for Simulations of LowResolution G-Protein-Coupled Receptor/Ligand Complexes Thomas Tarenzi†‡§, Vania Calandrini§*, Raffaello Potestio||*, Paolo Carloni‡§¶.
† Computation-based Science and Technology Research Center CaSToRC, The Cyprus Institute, 20 Konstaninou Kavafi street, 2121 Aglantzia, Nicosia, Cyprus.
‡ Departments of Physics, Faculty of Mathematics, Computer Science and Natural Sciences, Aachen University, Otto-Blumenthal Straße, 52062 Aachen, Germany.
§ Computational Biomedicine, Institute for Advanced Simulations IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52428 Jülich, Germany.
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Department
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Povo, Trento 38123, Italy, and INFN-TIFPA, Trento Institute for Fundamental Physics and Applications, I-38123 Trento, Italy.
¶ JARA-HPC, Jülich Supercomputing Center, Forschungszentrum Jülich, 52428 Jülich, Germany.
Keywords Ligand poses in GPCRs, coarse-grained models, multiscale simulations, grand canonical ensemble.
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Abstract
G-protein-coupled receptors (GPCRs) constitute as much as 30% of the overall proteins targeted by FDA-approved drugs. However, paucity of structural experimental information and low sequence identity between members of the family impair the reliability of traditional docking approaches and atomistic molecular dynamics simulations for in silico pharmacological applications. We present here a dual-resolution approach tailored for such low-resolution models. It couples a hybrid Molecular Mechanics/Coarse-Grained (MM/CG) scheme, previously developed by us for GPCR/ligand complexes, with a Hamiltonianbased Adaptive Resolution Scheme (H-AdResS) for the solvent. This dualresolution approach removes potentially inaccurate atomistic details from the model, while building a rigorous statistical ensemble - the grand canonical one - in the high-resolution region. We validate the method on a well-studied GPCR/ligand complex, for which the 3D-structure is known, against atomistic simulations. This implementation paves the way for future accurate in silico studies of low-resolution ligand/GPCRs models.
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Introduction
Membrane proteins constitute as much as 60% of the overall proteins targeted by FDA-approved drugs1. Among them, G-protein-coupled receptors (hGPCRs)2-3 are the largest family, comprising more than 800 members4, and the most important one from a pharmaceutical perspective5-7. Unfortunately, the lack of experimental structural information for most (more than 90%) hGPCRs8-9, along with low sequence identity (SI) across these proteins (often below 30%10-11) has hampered rational design efforts for many highly promising hGPCRs drug targets. For instance, 99% hGPCRs have an SI
