Identification of Electrostatic Epitopes in Flavivirus by Computer Simulations: The PROCEEDpKa Method

Author(s)

Poveda-Cuevas, Sergio A. ^{[1, 2]} ; Etchebest, Catherine ^{[3, 4, 5, 6]} ; Barroso da Silva, Fernando L. ^{[7, 1, 2, 4]}

Affiliation

^[1] Univ Sao Paulo, Programa Interunidades Bioinformat, Rua Matao 1010, BR-05508090 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Dept Ciencias Biomol, Fac Ciencias Farmacaut Ribeirao Preto, Av Cafe S-N, Campus USP, BR-14040903 Ribeirao Preto, SP - Brazil

^[3] Lab Excellence GR Ex, Paris - France

^[4] Univ Sao Paulo, Univ Sorbonne Paris Cite, Int Lab Struct Bioinformat, Av Cafe S-N FCFRP, Bloco B, BR-14040903 Ribeirao Preto, SP - Brazil

^[5] Univ Paris, Biol Integree Globule Rouge, UMR S1134, BIGR, INSERM, F-75015 Paris - France

^[6] Univ Paris Diderot Paris 7, Dynam Struct & Interact Mol, Equipe 2, INTS, 6 Rue Alexandre Cabanel, F-75015 Paris - France

^[7] North Carolina State Univ, Dept Chem & Biomol Engn, Raleigh, NC 27695 - USA

• Document type: Journal article
• Source: JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 944-963, FEB 2020.
• Web of Science Citations: 1

Abstract

Viruses are enthusiastically studied due to the great impact that these organisms can have on human health. Computational approaches can contribute offering tools that can shed light on important molecular mechanisms that help to design new diagnostic procedures. Several cellular processes between the immune-host system and the pathogenic organism are dependent on specific intermolecular interactions. In this study, we evaluated theoretical approaches to understand some properties of the antigen antibody interactions considering the titratable properties of all ionizable residues of the nonstructural viral protein 1 (NSI) of the West Nile virus (WNV) and the Zika virus (ZIKV). Constant-pH Monte Carlo simulations were performed to estimate electrostatic properties such as the pK(a) shifts (Delta pK(a)). We proposed an alternative criterion for the discrimination of antigenic residues based on Delta pK(a)s. Our outcomes were analyzed by an evaluation of the sensitivity and specificity through a receiver operating characteristic (ROC). As a starting point, we used the known crystallographic structure for the complex of NS1(WNV(176-352)) and the specific antibody 22NS1 (PDB ID 4011) to differentiate the residues belonging to that interface. With an optimal threshold for the absolute value of the pKa shifts, we found that is possible to predict antigenic epitopes reproducing the interfaces as defined by the X-ray structure. After this validation, we evaluated theoretical predictions based on protein protein (PP) complexation simulations. From them, we observe amino acids with an antigenic potential and defined the optimum threshold that was applied for two strains of ZIKV (i.e., Uganda and Brazil). Several ionizable residues with antigenic capacity were identified. This is favorably related to some studies that show the high immunogenicity of secreted NS1. This approach opens up an important discussion about what are termed here ``electrostatic epitopes{''} and how they work as an important reference in the paratope epitope interaction for viral systems. (AU)

• FAPESP's process: 19/06139-7 - 8th International Conference on Bioengineering and Nanotechnology
• Grantee: Fernando Luis Barroso da Silva
• Support Opportunities: Research Grants - Meeting - Abroad
• FAPESP's process: 15/16116-3 - Molecular mechanisms of electrostatic origin responsible for protein complexation
• Grantee: Fernando Luis Barroso da Silva
• Support Opportunities: Regular Research Grants