Dataset Information

Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In Silico Approaches Based on Unbiased Molecular Dynamics Simulations.

ABSTRACT: Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (e.g., mutations). To accurately model allostery, unbiased molecular dynamics (MD) simulations require integration with a reliable method able to, e.g., detect incipient allosteric changes or likely perturbation pathways; this is because allostery can operate at longer time scales than those accessible by plain MD. Such methods are typically applied singularly, but we here argue their joint application─as a "multilingual" approach─could work significantly better. We successfully prove this through unbiased MD simulations (∼100 μs) of the widely studied, allosterically active oncotarget K-Ras4B, solvated and embedded in a phospholipid membrane, from which we decrypt allostery using four showcase "languages": Distance Fluctuation analysis and the Shortest Path Map capture allosteric hotspots at equilibrium; Anisotropic Thermal Diffusion and Dynamical Non-Equilibrium MD simulations assess perturbations upon, respectively, either superheating or hydrolyzing the GTP that oncogenically activates K-Ras4B. Chosen "languages" work synergistically, providing an articulate, mutually coherent, experimentally consistent picture of K-Ras4B allostery, whereby distinct traits emerge at equilibrium and upon GTP cleavage. At equilibrium, combined evidence confirms prominent allosteric communication from the membrane-embedded hypervariable region, through a hub comprising helix α5 and sheet β5, and up to the active site, encompassing allosteric "switches" I and II (marginally), and two proposed pockets. Upon GTP cleavage, allosteric perturbations mostly accumulate on the switches and documented interfaces.

SUBMITTER: Castelli M

PROVIDER: S-EPMC10785808 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Publications

Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In Silico Approaches Based on Unbiased Molecular Dynamics Simulations.

Castelli Matteo M Marchetti Filippo F Osuna Sílvia S F Oliveira A Sofia AS Mulholland Adrian J AJ Serapian Stefano A SA Colombo Giorgio G

Journal of the American Chemical Society 20231220 1

Protein functions are dynamically regulated by allostery, which enables conformational communication even between faraway residues, and expresses itself in many forms, akin to different "languages": allosteric control pathways predominating in an unperturbed protein are often unintuitively reshaped whenever biochemical perturbations arise (e.g., mutations). To accurately model allostery, unbiased molecular dynamics (MD) simulations require integration with a reliable method able to, e. ...[more]

PMID: 38116743

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Project description:Membrane-bound transcription factors (MTFs) are located in cellular membranes due to their transmembrane domains. In plants, proteolytic processing is considered to be the main mechanism for MTF activation, which ensures the liberation of MTFs from membranes and further their translocation into the nucleus to regulate gene expression; this process skips both the transcriptional and translational stages, and thus it guarantees the prompt responses of plants to various stimuli. Currently, information concerning plant MTFs is limited to model organisms, including Arabidopsis thaliana and Oryza sativa, and little is known in other plant species at the genome level. In the present study, seven membrane topology predictors widely used by the research community were employed to establish a reliable workflow for MTF identification. Genome-wide in silico analysis of MTFs was then performed in 14 plant species spanning the chlorophytes, bryophytes, gymnosperms, monocots and eudicots. A total of 1,089 MTFs have been identified from a total of 25,850 transcription factors in these 14 plant species. These MTFs belong to 52 gene family, and the top six most abundant families are the NAC (128), SBP (77), C2H2 (70), bZIP (67), MYB-related (65) and bHLH (63) families. The MTFs have transmembrane spans ranging from one to thirteen, and 71.5% and 21.1% of the MTFs have one and two transmembrane motifs, respectively. Most of the MTFs in this study have transmembrane motifs located in either N- or C-terminal regions, indicating that proteolytic cleavage could be a conserved mechanism for MTF activation. Additionally, approximately half of the MTFs in the genome of either Arabidopsis thaliana or Gossypium raimondii could be potentially regulated by alternative splicing, indicating that alternative splicing is another conserved activation mechanism for MTFs. The present study performed systematic analyses of MTFs in plant lineages at the genome level, and provides invaluable information for the research community.

Dataset Information

Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary In Silico Approaches Based on Unbiased Molecular Dynamics Simulations.

Publications

Decrypting Allostery in Membrane-Bound K-Ras4B Using Complementary <i>In Silico</i> Approaches Based on Unbiased Molecular Dynamics Simulations.

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