Development of OPLS-AA/M Parameters for Simulations of G Protein-Coupled Receptors and Other Membrane Proteins

Dynamic Nature ◽

Post Translational Modifications ◽

Dynamics Simulations ◽

High Level ◽

G protein-coupled receptors (GPCRs) and other membrane proteins are valuable drug targets, and their dynamic nature makes them attractive systems for study with molecular dynamics simulations and free energy approaches. Here, we report the development, implementation, and validation of OPLS-AA/M force field parameters to enable simulations of these systems. These efforts include the introduction of post-translational modifications including lipidations and phosphorylation. We also modify previously reported parameters for lipids to be more consistent with the OPLS-AA force field standard and extend their coverage. These new parameters are validated on a variety of test systems, with the results compared to high-level quantum mechanics calculations, experimental data, and simulations with CHARMM36m where relevant. The results demonstrate that the new parameters reliably reproduce the behavior of membrane protein systems.

Showcasing modern molecular dynamics simulations of membrane proteins through G protein-coupled receptors

Current Opinion in Structural Biology ◽

10.1016/j.sbi.2011.06.008 ◽

2011 ◽

Vol 21 (4) ◽

pp. 552-558 ◽

Cited By ~ 56

Author(s):

Jennifer M Johnston ◽

Marta Filizola

Keyword(s):

Molecular Dynamics ◽

Membrane Proteins ◽

Molecular Dynamics Simulations ◽

G Protein ◽

Dynamics Simulations ◽

Lipid nanoparticle technologies for the study of G protein-coupled receptors in lipid environments

Biophysical Reviews ◽

10.1007/s12551-020-00775-5 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1287-1302 ◽

Cited By ~ 1

Author(s):

Steven Lavington ◽

Anthony Watts

Keyword(s):

Membrane Proteins ◽

G Protein ◽

Drug Targets ◽

Large Family ◽

Integral Membrane Proteins ◽

Lipid Nanoparticle ◽

Wide Range ◽

Biophysical Studies ◽

AbstractG protein-coupled receptors (GPCRs) are a large family of integral membrane proteins which conduct a wide range of biological roles and represent significant drug targets. Most biophysical and structural studies of GPCRs have been conducted on detergent-solubilised receptors, and it is clear that detergents can have detrimental effects on GPCR function. Simultaneously, there is increasing appreciation of roles for specific lipids in modulation of GPCR function. Lipid nanoparticles such as nanodiscs and styrene maleic acid lipid particles (SMALPs) offer opportunities to study integral membrane proteins in lipid environments, in a form that is soluble and amenable to structural and biophysical experiments. Here, we review the application of lipid nanoparticle technologies to the study of GPCRs, assessing the relative merits and limitations of each system. We highlight how these technologies can provide superior platforms to detergents for structural and biophysical studies of GPCRs and inform on roles for protein-lipid interactions in GPCR function.

Synthetic GPCRs and signal transduction cascades

Emerging Topics in Life Sciences ◽

10.1042/etls20190035 ◽

2019 ◽

Vol 3 (5) ◽

pp. 609-614 ◽

Cited By ~ 1

Author(s):

Colleen Mulvihill ◽

Andrew Ellington

Keyword(s):

Signal Transduction ◽

Synthetic Biology ◽

Membrane Proteins ◽

G Protein ◽

Drug Targets ◽

Complex Signal ◽

Diverse Group ◽

Orthogonal Components ◽

G protein-coupled receptors (GPCRs) are a large and diverse group of membrane proteins that constitute over 30% of FDA approved drug targets. Despite their importance, much remains unknown about GPCR signaling at a system's level. Efforts to engineer receptors with orthogonal components have attempted to provide tools to parse signaling and resultant phenotypes. Recent advances in synthetic biology provide opportunities to engineer receptors at scale and with additional properties that could further inform GPCR biology at a system's level, and enhance the ability to engineer complex signal transduction.

Dynamical Correlations Reveal Allosteric Sites in G Protein-Coupled Receptors

International Journal of Molecular Sciences ◽

10.3390/ijms22010187 ◽

2020 ◽

Vol 22 (1) ◽

pp. 187

Author(s):

Pedro Renault ◽

Jesús Giraldo

Keyword(s):

G Protein ◽

Conformational Changes ◽

Drug Targets ◽

Normal Mode Analysis ◽

Mode Analysis ◽

Allosteric Sites ◽

Basic Hypothesis ◽

Dynamics Simulations ◽

G protein-coupled Receptors (GPCRs) play a central role in many physiological processes and, consequently, constitute important drug targets. In particular, the search for allosteric drugs has recently drawn attention, since they could be more selective and lead to fewer side effects. Accordingly, computational tools have been used to estimate the druggability of allosteric sites in these receptors. In spite of many successful results, the problem is still challenging, particularly the prediction of hydrophobic sites in the interface between the protein and the membrane. In this work, we propose a complementary approach, based on dynamical correlations. Our basic hypothesis was that allosteric sites are strongly coupled to regions of the receptor that undergo important conformational changes upon activation. Therefore, using ensembles of experimental structures, normal mode analysis and molecular dynamics simulations we calculated correlations between internal fluctuations of different sites and a collective variable describing the activation state of the receptor. Then, we ranked the sites based on the strength of their coupling to the collective dynamics. In the β2 adrenergic (β2AR), glucagon (GCGR) and M2 muscarinic receptors, this procedure allowed us to correctly identify known allosteric sites, suggesting it has predictive value. Our results indicate that this dynamics-based approach can be a complementary tool to the existing toolbox to characterize allosteric sites in GPCRs.

The relevance of adhesion G protein-coupled receptors in metabolic functions

Biological Chemistry ◽

10.1515/hsz-2021-0146 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Isabell Kaczmarek ◽

Tomáš Suchý ◽

Simone Prömel ◽

Torsten Schöneberg ◽

Ines Liebscher ◽

...

Keyword(s):

G Protein ◽

Drug Targets ◽

Metabolic Diseases ◽

Current Knowledge ◽

Specific Expression ◽

Physiological Functions ◽

Metabolic Functions ◽

Central Nervous Systems ◽

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.