Investigação computacional do mecanismo catalítico da nsP2 do vírus Chikungunya (CHIKV)

Abstract

The nsP2 protein of the Chikungunya virus (CHIKV) is a cysteine protease essential for the formation of the viral replication complex. Therefore, understanding its molecular mechanism is crucial for the development of novel inhibitors. In this dissertation, we exclusively investigate the enzymatic activation mechanism of nsP2 through molecular dynamics (MD) simulations using a cluster approach, as well as quantum mechanics (QM) calculations to study the enzymatic reaction within the active site. Specifically, we analyze the activation of the catalytic dyad Cys478-His548 and assess the influence of a water molecule on this process. When a water molecule is present, the distance between Cys478and His548 in the transition state is 1.96 Å (SH∙∙∙OH₂) and 1.28 Å (N∙∙∙H₂O). Additionally, activation energy calculations indicate that the presence of water lowers the energy barrier by approximately 7 kcal/mol, facilitating the enzyme activation mechanism. Based on these findings, we propose a model for a possible reaction pathway, including the transition state for proton transfer in the formation of the ion pair Cys(S⁻)/His(NH⁺). Understanding this mechanism at the molecular level allows for the identification of critical points in nsP2 function that can be explored in the design of specific inhibitors. Thus, our findings provide a solid foundation for the rational development of compounds with potential applications in the treatment of Chikungunya fever.