Multiscale Computational Protocols for Accurate Residue Interactions at the Flexible Insulin-Receptor Interface

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00635637" target="_blank" >RIV/61388963:_____/25:00635637 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.1021/acs.jcim.5c00772" target="_blank" >https://doi.org/10.1021/acs.jcim.5c00772</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jcim.5c00772" target="_blank" >10.1021/acs.jcim.5c00772</a>

Result language

angličtina

Original language name

Multiscale Computational Protocols for Accurate Residue Interactions at the Flexible Insulin-Receptor Interface

Original language description

The quantitative characterization of residue contributions to protein-protein binding across extensive flexible interfaces poses a significant challenge for biophysical computations. It is attributable to the inherent imperfections in the experimental structures themselves, as well as to the lack of reliable computational tools for the evaluation of all types of noncovalent interactions. This study leverages recent advancements in semiempirical quantum-mechanical and implicit solvent approaches embodied in the PM6-D3H4S/COSMO2 method for the development of a hierarchical computational protocols encompassing molecular dynamics, fragmentation, and virtual glycine scan techniques for the investigation of flexible protein-protein interactions. As a model, the binding of insulin to its receptor is selected, a complex and dynamic process that has been extensively studied experimentally. The interaction energies calculated at the PM6-D3H4S/COSMO2 level in ten molecular dynamics snapshots did not correlate with molecular mechanics/generalized Born interaction energies because only the former method is able to describe nonadditive effects. This became evident by the examination of the energetics in small-model dimers featuring all the present types of noncovalent interactions with respect to DFT-D3 calculations. The virtual glycine scan has identified 15 hotspot residues on insulin and 15 on the insulin receptor, and their contributions have been quantified using PM6-D3H4S/COSMO2. The accuracy and credibility of the approach are further supported by the fact that all the insulin hotspots have previously been detected by biochemical and structural methods. The modular nature of the protocol has enabled the formulation of several variants, each tailored to specific accuracy and efficiency requirements. The developed computational strategy is firmly rooted in general biophysical chemistry and is thus offered as a general tool for the quantification of interactions across relevant flexible protein-protein interfaces.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10610 - Biophysics

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Journal of Chemical Information and Modeling

ISSN

1549-9596

e-ISSN

1549-960X

Volume of the periodical

65

Issue of the periodical within the volume

11

Country of publishing house

US - UNITED STATES

Number of pages

16

Pages from-to

5690-5705

UT code for WoS article

001490103700001

EID of the result in the Scopus database

2-s2.0-105005263175