Deep learning for discriminating non-trivial conformational changes in molecular dynamics simulations of SARS-CoV-2 spike-ACE2.

Autor: Moraes Dos Santos L; Department of Computer Science, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. lucas.santos@dcc.ufmg.br., Gutembergue de Mendonça J; Department of Chemistry, Federal University of Paraíba, João Pessoa, Paraíba, Brazil., Jerônimo Gomes Lobo Y; Department of Exact and Biological Sciences, Federal University of São João Del Rei, São João del Rei, Minas Gerais, Brazil., Henrique Franca de Lima L; Department of Exact and Biological Sciences, Federal University of São João Del Rei, São João del Rei, Minas Gerais, Brazil., Bruno Rocha G; Department of Chemistry, Federal University of Paraíba, João Pessoa, Paraíba, Brazil., C de Melo-Minardi R; Department of Computer Science, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. raquelcm@dcc.ufmg.br.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Sep 30; Vol. 14 (1), pp. 22639. Date of Electronic Publication: 2024 Sep 30.
DOI: 10.1038/s41598-024-72842-w
Abstrakt: Molecular dynamics (MD) simulations produce a substantial volume of high-dimensional data, and traditional methods for analyzing these data pose significant computational demands. Advances in MD simulation analysis combined with deep learning-based approaches have led to the understanding of specific structural changes observed in MD trajectories, including those induced by mutations. In this study, we model the trajectories resulting from MD simulations of the SARS-CoV-2 spike protein-ACE2, specifically the receptor-binding domain (RBD), as interresidue distance maps, and use deep convolutional neural networks to predict the functional impact of point mutations, related to the virus's infectivity and immunogenicity. Our model was successful in predicting mutant types that increase the affinity of the S protein for human receptors and reduce its immunogenicity, both based on MD trajectories (precision = 0.718; recall = 0.800; [Formula: see text] = 0.757; MCC = 0.488; AUC = 0.800) and their centroids. In an additional analysis, we also obtained a strong positive Pearson's correlation coefficient equal to 0.776, indicating a significant relationship between the average sigmoid probability for the MD trajectories and binding free energy (BFE) changes. Furthermore, we obtained a coefficient of determination of 0.602. Our 2D-RMSD analysis also corroborated predictions for more infectious and immune-evading mutants and revealed fluctuating regions within the receptor-binding motif (RBM), especially in the [Formula: see text] loop. This region presented a significant standard deviation for mutations that enable SARS-CoV-2 to evade the immune response, with RMSD values of 5Å in the simulation. This methodology offers an efficient alternative to identify potential strains of SARS-CoV-2, which may be potentially linked to more infectious and immune-evading mutations. Using clustering and deep learning techniques, our approach leverages information from the ensemble of MD trajectories to recognize a broad spectrum of multiple conformational patterns characteristic of mutant types. This represents a strategic advantage in identifying emerging variants, bypassing the need for long MD simulations. Furthermore, the present work tends to contribute substantially to the field of computational biology and virology, particularly to accelerate the design and optimization of new therapeutic agents and vaccines, offering a proactive stance against the constantly evolving threat of COVID-19 and potential future pandemics.
(© 2024. The Author(s).)
Databáze: MEDLINE
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