Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease

• Type: Article in International Scientific Journal
• Date: 2022

Authors

Coimbra, JTS (Author) Other; Neves, RPP (Author) FCUP; Cunha, AV (Author) Other; Ramos, MJ (Author) FCUP; Pedro A Fernandes (Author) FCUP

Journal

Title: Chemistry - A European Journal

Vol. 28

ISSN: 0947-6539

Publisher: Wiley-Blackwell

Indexing

ISI Web of Knowledge - 0 Citations

Scopus

Other information

Authenticus ID: P-00W-SPF

DOI: 10.1002/chem.202201066

Abstract (EN): The influence of the dynamical flexibility of enzymes on reaction mechanisms is a cornerstone in biological sciences. In this study, we aim to 1) study the convergence of the activation free energy by using the first step of the reaction catalysed by HIV-1 protease as a case study, and 2) provide further evidence for a mechanistic divergence in this enzyme, as two different reaction pathways were seen to contribute to this step. We used quantum mechanics/molecular mechanics molecular dynamics simulations, on four different initial conformations that led to different barriers in a previous study. Despite the sampling, the four activation free energies still spanned a range of 5.0 kcal . mol(-1). Furthermore, the new simulations did confirm the occurrence of an unusual mechanistic divergence, with two different mechanistic pathways displaying equivalent barriers. An active-site water molecule is proposed to influence the mechanistic pathway.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 8