ABSTRACT
Evolutionarily related proteins can present similar structures but very dissimilar sequences. Hence, understanding the role of the inter-residues contacts for the protein structure has been the target of many studies. Contacts comprise non-covalent interactions, which are essential to stabilize macromolecular structures such as proteins. Here we show VTR, a new method for the detection of analogous contacts in protein pairs. The VTR web tool performs structural alignment between proteins and detects interactions that occur in similar regions. To evaluate our tool, we proposed three case studies: we 1) compared vertebrate myoglobin and truncated invertebrate hemoglobin; 2) analyzed interactions between the spike protein RBD of SARS-CoV-2 and the cell receptor ACE2; and 3) compared a glucose-tolerant and a non-tolerant ß-glucosidase enzyme used for biofuel production. The case studies demonstrate the potential of VTR for the understanding of functional similarities between distantly sequence-related proteins, as well as the exploration of important drug targets and rational design of enzymes for industrial applications. We envision VTR as a promising tool for understanding differences and similarities between homologous proteins with similar 3D structures but different sequences. VTR is available at http://bioinfo.dcc.ufmg.br/vtr.
ABSTRACT
Background: 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. Methods: 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. Results: 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. Discussion: 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'/ß1', 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.