Laboratory of Bioinformatics and Systems, Institute of Exact Sciences, Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
Laboratory of Quantum and Computational Chemistry, Center of Exact and Natural Sciences, Department of Chemistry, Universidade Federal da Paraíba, João Pessoa, PB, Brazil.
PeerJ. 2022 Mar 22;10:e13099. doi: 10.7717/peerj.13099. eCollection 2022.
The SARS-CoV-2 pandemic reverberated, posing health and social hygiene obstacles throughout the globe. Mutant lineages of the virus have concerned scientists because of convergent amino acid alterations, mainly on the viral spike protein. Studies have shown that mutants have diminished activity of neutralizing antibodies and enhanced affinity with its human cell receptor, the ACE2 protein.
Hence, for real-time measuring of the impacts caused by variant strains in such complexes, we implemented E-Volve, a tool designed to model a structure with a list of mutations requested by users and return analyses of the variant protein. As a proof of concept, we scrutinized the spike-antibody and spike-ACE2 complexes formed in the variants of concern, B.1.1.7 (Alpha), B.1.351 (Beta), and P.1 (Gamma), by using contact maps depicting the interactions made amid them, along with heat maps to quantify these major interactions.
The results found in this study depict the highly frequent interface changes made by the entire set of mutations, mainly conducted by N501Y and E484K. In the spike-Antibody complex, we have noticed alterations concerning electrostatic surface complementarity, breaching essential sites in the P17 and BD-368-2 antibodies. Alongside, the spike-ACE2 complex has presented new hydrophobic bonds.
Molecular dynamics simulations followed by Poisson-Boltzmann calculations corroborate the higher complementarity to the receptor and lower to the antibodies for the K417T/E484K/N501Y (Gamma) mutant compared to the wild-type strain, as pointed by E-Volve, as well as an intensification of this effect by changes at the protein conformational equilibrium in solution. A local disorder of the loop α1'/β1', as well its possible effects on the affinity to the BD-368-2 antibody were also incorporated to the final conclusions after this analysis. Moreover, E-Volve can depict the main alterations in important biological structures, as shown in the SARS-CoV-2 complexes, marking a major step in the real-time tracking of the virus mutant lineages. E-Volve is available at http://bioinfo.dcc.ufmg.br/evolve.
SARS-CoV-2 大流行引起了全球范围的健康和社会卫生问题。病毒的突变株引起了科学家的关注，因为它们在病毒刺突蛋白上存在趋同的氨基酸变化。研究表明，突变株的中和抗体活性降低，与病毒的人类细胞受体 ACE2 蛋白的亲和力增强。
因此，为了实时测量变异株在这些复合物中引起的影响，我们开发了 E-Volve，这是一种设计用于对用户请求的突变列表建模并返回变异蛋白分析的工具。作为概念验证，我们使用接触图描绘了它们之间的相互作用，并使用热图量化了这些主要相互作用，仔细研究了在关注的变异株 B.1.1.7（阿尔法）、B.1.351（贝塔）和 P.1（伽马）中形成的刺突-抗体和刺突-ACE2 复合物。
本研究发现的结果描绘了整个突变集引起的高度频繁的界面变化，主要由 N501Y 和 E484K 引起。在刺突-抗体复合物中，我们注意到与静电表面互补性有关的变化，破坏了 P17 和 BD-368-2 抗体的关键部位。同时，刺突-ACE2 复合物出现了新的疏水键。
泊松-玻尔兹曼计算的分子动力学模拟证实了 E-Volve 指出的 K417T/E484K/N501Y（伽马）突变体与野生型相比对受体的互补性更高，对抗体的互补性更低，以及在溶液中蛋白质构象平衡变化的情况下，这种效应的增强。分析后，还将α1'/β1'环的局部无序及其对 BD-368-2 抗体亲和力的可能影响纳入最终结论。此外，E-Volve 可以描绘 SARS-CoV-2 复合物等重要生物结构的主要变化，这标志着实时跟踪病毒突变株的重要一步。E-Volve 可在 http://bioinfo.dcc.ufmg.br/evolve 获得。
