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Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures.

ABSTRACT: The opioid receptors are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of opioid receptors have provided a wealth of knowledge on many aspects of opioid receptor pharmacology and function, including ligand binding poses, location of the sodium allosteric binding site, conformational changes associated with activation and putative dimeric interfaces. These crystal structures also offer a starting point for molecular dynamics (MD) simulations to capture one aspect of drug design that static structures cannot resolve, namely protein dynamics. With the increase in computing power, MD simulations of crystal structures have become an influential tool in understanding the function of GPCRs in general. Here, we discuss lessons learned from MD simulations of opioid receptor crystal structures with reference to (i) the binding pathway of sodium to its crystallographic allosteric site, (ii) the dynamics of ligand-receptor and receptor-receptor interactions, both at the ligand- and G protein-binding sites, (iii) the binding pathway and binding pose of novel ligands, and (iv) opioid receptor oligomerization. LINKED ARTICLES:This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

SUBMITTER: Marino KA

PROVIDER: S-EPMC6016634 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures.

Marino Kristen A KA Shang Yi Y Filizola Marta M

British journal of pharmacology 20170412 14

The opioid receptors are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of opioid receptors have provided a wealth of knowledge on many aspects of opioid receptor pharmacology and function, including ligand binding poses, location of the sodium allosteric binding site, conformational changes associated with activation and putative dimeric inte ...[more]

PMID: 28266020

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Project description:The function of proteins is influenced not only by the atomic structure but also by the detailed structure of the solvent surrounding it. Computational studies of protein structure also critically depend on the water structure around the protein. Herein we compare the water structure obtained from molecular dynamics (MD) simulations of galectin-3 in complex with two ligands to crystallographic water molecules observed in the corresponding crystal structures. We computed MD trajectories both in a water box, which mimics a protein in solution, and in a crystallographic unit cell, which mimics a protein in a crystal. The calculations were compared to crystal structures obtained at both cryogenic and room temperature. Two types of analyses of the MD simulations were performed. First, the positions of the crystallographic water molecules were compared to peaks in the MD density after alignment of the protein in each snapshot. The results of this analysis indicate that all simulations reproduce the crystallographic water structure rather poorly. However, if we define the crystallographic water sites based on their distances to nearby protein atoms and follow these sites throughout the simulations, the MD simulations reproduce the crystallographic water sites much better. This shows that the failure of MD simulations to reproduce the water structure around proteins in crystal structures observed both in this and previous studies is caused by the problem of identifying water sites for a flexible and dynamic protein (traditionally done by overlaying the structures). Our local clustering approach solves the problem and shows that the MD simulations reasonably reproduce the water structure observed in crystals. Furthermore, analysis of the crystal MD simulations indicates a few water molecules that are close to unmodeled electron density peaks in the crystal structures, suggesting that crystal MD could be used as a complementary tool for identifying and modelling water in protein crystallography.

Dataset Information

Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures.

Publications

Insights into the function of opioid receptors from molecular dynamics simulations of available crystal structures.

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