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Open AccessArticle

Hot Spots and Their Contribution to the Self-Assembly of the Viral Capsid: In Silico Prediction and Analysis

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Biomolecular Diversity Laboratory, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional Unidad Monterrey, Vía del Conocimiento 201, Parque PIIT, C.P. 66600 Apodaca, Nuevo León, Mexico
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Unidad Profesional Interdisciplinaria de Ingeniería Campus Guanajuato, Instituto Politécnico Nacional, Av. Mineral de Valenciana No. 200, Col. Fraccionamiento Industrial Puerto Interior, C.P. 36275 Silao de la Victoria, Guanajuato, Mexico
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Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 5966; https://doi.org/10.3390/ijms20235966
Received: 12 October 2019 / Revised: 11 November 2019 / Accepted: 15 November 2019 / Published: 27 November 2019
(This article belongs to the Special Issue Designer Biopolymers: Self-Assembling Proteins and Nucleic Acids 2020)
The viral capsid is a macromolecular complex formed by a defined number of self-assembled proteins, which, in many cases, are biopolymers with an identical amino acid sequence. Specific protein–protein interactions (PPI) drive the capsid self-assembly process, leading to several distinct protein interfaces. Following the PPI hot spot hypothesis, we present a conservation-based methodology to identify those interface residues hypothesized to be crucial elements on the self-assembly and thermodynamic stability of the capsid. We validate the predictions through a rigorous physical framework which integrates molecular dynamics simulations and free energy calculations by Umbrella sampling and the potential of mean force using an all-atom molecular representation of the capsid proteins of an icosahedral virus in an explicit solvent. Our results show that a single mutation in any of the structure-conserved hot spots significantly perturbs the quaternary protein–protein interaction, decreasing the absolute value of the binding free energy, without altering the protein’s secondary nor tertiary structure. Our conservation-based hot spot prediction methodology can lead to strategies to rationally modulate the capsid’s thermodynamic properties. View Full-Text
Keywords: free energy; structural conservation; functional dimer; protein–protein interaction; site-directed mutagenesis; binding free energy; molecular dynamics; alanine-scanning free energy; structural conservation; functional dimer; protein–protein interaction; site-directed mutagenesis; binding free energy; molecular dynamics; alanine-scanning
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Díaz-Valle, A.; Falcón-González, J.M.; Carrillo-Tripp, M. Hot Spots and Their Contribution to the Self-Assembly of the Viral Capsid: In Silico Prediction and Analysis. Int. J. Mol. Sci. 2019, 20, 5966.

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