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The structural basis for the pharmacology of human G protein-coupled receptors (GPCRs), the most abundant membrane proteins and the target of about 35% of approved drugs, is still a matter of intense study. What makes GPCRs challenging to study is the inherent flexibility and the metastable nature of interaction with extra- and intracellular partners that drive their effects. Here, we present a molecular dynamics (MD) adaptive sampling algorithm, namely multiple walker supervised molecular dynamics (mwSuMD), to address complex structural transitions involving GPCRs without energy input. We first report the binding and unbinding of the vasopressin peptide from its receptor V2. Successively, we present the complete transition of the glucagon-like peptide-1 receptor (GLP-1R) from inactive to active, agonist and Gs-bound state, and the guanosine diphosphate (GDP) release from Gs. To our knowledge, this is the first time the whole sequence of events leading from an inactive GPCR to the GDP release is simulated without any energy bias. We demonstrate that mwSuMD can address complex binding processes intrinsically linked to protein dynamics out of reach of classic MD.
Pubmed ID: 40305095
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The GPCRDB is a molecular-class information system that collects, combines, validates and stores large amounts of heterogenous data on G protein-coupled receptors (GPCRs). :The GPCRDB contains data on sequences, ligand binding constants and mutations. In addition, t he system provides computationally derived data such as multiple sequence alignments, homology models, and a series of query and visualization tools. :The GPCRDB is designed to be a data storage medium, as well as a tool to aid biomedical scientists with answering questions by offering a single point of access to many types of data that are integrated and visualized in a user-friendly way. Although most parts of the GPCRDB are self-explanatory, if you have not used this resource before it is adviced that you to take a look at the usage page. Sponsors: This resource is supported by Organon and Unilever, and the NIH. Keywords: G protein, Coupled, receptor, Molecular, Heterogenous, Data, Sequence, Ligand, Mutation, Computational, Software, Alignment, Homology, Model, Visualization, Tool, Biomedical, Scientist, Integration,
View all literature mentionsSoftware tool as Program for Comparative Protein Structure Modelling by Satisfaction of Spatial Restraints. Used for homology or comparative modeling of protein three dimensional structures. User provides alignment of sequence to be modeled with known related structures and MODELLER automatically calculates model containing all non hydrogen atoms.
View all literature mentionsSoftware package of molecular simulation programs. It is distributed into AmberTools15 and Amber14. AmberTools15 is a software package which can carry out complete molecular dynamics simulations with either explicit water or generalized Born solvent models. It is distributed in source code format and must be compiled in order to be used. Amber14 builds on AmberTools15 by adding the pmemd program, which provides better performance on multiple CPUs and dramatic speed improvements on GPUs compared to sander (molecular dynamics). GPU info, manuals, and tutorials are available on the website.
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