Dataset Information

Origin of Correlations between Local Conformational States of Consecutive Amino Acid Residues and Their Role in Shaping Protein Structures and in Allostery.

ABSTRACT: By analyzing the Kubo-cluster-cumulant expansion of the potential of mean force of polypeptide chains corresponding to backbone-local interactions averaged over the rotation of the peptide groups about the C^α···C^α virtual bonds, we identified two important kinds of "along-chain" correlations that pertain to extended chain segments bordered by turns (usually the β-strands) and to the folded spring-like segments (usually α-helices), respectively, and are expressed as multitorsional potentials. These terms affect the positioning of structural elements with respect to each other and, consequently, contribute to determining their packing. Additionally, for extended chain segments, the correlation terms contribute to propagating the conformational change at one end to the other end, which is characteristic of allosteric interactions. We confirmed both findings by statistical analysis of the virtual-bond geometry of 77 950 proteins. Augmenting coarse-grained and, possibly, all-atom force fields with these correlation terms could improve their capacity to model protein structure and dynamics.

SUBMITTER: Sikorska C

PROVIDER: S-EPMC9706564 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Origin of Correlations between Local Conformational States of Consecutive Amino Acid Residues and Their Role in Shaping Protein Structures and in Allostery.

Sikorska Celina C Liwo Adam A

The journal of physical chemistry. B 20221111 46

By analyzing the Kubo-cluster-cumulant expansion of the potential of mean force of polypeptide chains corresponding to backbone-local interactions averaged over the rotation of the peptide groups about the C<sup>α</sup>···C<sup>α</sup> virtual bonds, we identified two important kinds of "along-chain" correlations that pertain to extended chain segments bordered by turns (usually the β-strands) and to the folded spring-like segments (usually α-helices), respectively, and are expressed as multitor ...[more]

PMID: 36367920

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Project description:Protein conformational changes and dynamic behavior are fundamental for such processes as catalysis, regulation, and substrate recognition. Although protein dynamics have been successfully explored in computer simulation, there is an intermediate-scale of motions that has proven difficult to simulate - the motion of individual segments or domains that move independently of the body the protein. Here, we introduce a molecular-dynamics perturbation method, the Rotamerically Induced Perturbation (RIP), which can generate large, coherent motions of structural elements in picoseconds by applying large torsional perturbations to individual sidechains. Despite the large-scale motions, secondary structure elements remain intact without the need for applying backbone positional restraints. Owing to its computational efficiency, RIP can be applied to every residue in a protein, producing a global map of deformability. This map is remarkably sparse, with the dominant sites of deformation generally found on the protein surface. The global map can be used to identify loops and helices that are less tightly bound to the protein and thus are likely sites of dynamic modulation that may have important functional consequences. Additionally, they identify individual residues that have the potential to drive large-scale coherent conformational change. Applying RIP to two well-studied proteins, Dihdydrofolate Reductase and Triosephosphate Isomerase, which possess functionally-relevant mobile loops that fluctuate on the microsecond/millisecond timescale, the RIP deformation map identifies and recapitulates the flexibility of these elements. In contrast, the RIP deformation map of alpha-lytic protease, a kinetically stable protein, results in a map with no significant deformations. In the N-terminal domain of HSP90, the RIP deformation map clearly identifies the ligand-binding lid as a highly flexible region capable of large conformational changes. In the Estrogen Receptor ligand-binding domain, the RIP deformation map is quite sparse except for one large conformational change involving Helix-12, which is the structural element that allosterically links ligand binding to receptor activation. RIP analysis has the potential to discover sites of functional conformational changes and the linchpin residues critical in determining these conformational states.

Dataset Information

Origin of Correlations between Local Conformational States of Consecutive Amino Acid Residues and Their Role in Shaping Protein Structures and in Allostery.

Publications

Origin of Correlations between Local Conformational States of Consecutive Amino Acid Residues and Their Role in Shaping Protein Structures and in Allostery.

Similar Datasets

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