Jump to main content
Jump to site search


Conformational Diversity Induces Nanosecond-Timescale Chemical Disorder in the HIV-1 Protease Reaction Pathway

Abstract

The role of conformational diversity on enzyme catalysis has been a matter of analysis on recent studies. Pre-organization of the active site has been pointed out as the major source for enzymes’ catalytic power. Within this line of thought, it is becoming clear that specific, instantaneous, non-rare enzyme conformations that make the active site perfectly pre-organized for the reaction, lead to the lowest activation barriers that mostly contribute to the macroscopic observed reaction rate. The present work is focused on exploring the relationship between structure and catalysis in HIV-1 protease (PR) with an adiabatic mapping method, starting from different initial structures, collected from a classical MD simulation. The first, rate-limiting step of HIV-1 PR catalytic mechanism was studied with the ONIOM QM/MM methodology (B3LYP/6-31G(d):ff99SB), with activation and reaction energies calculated at the M06-2X/6-311++G(2d,2p):ff99SB level of theory, in 19 different enzyme:substrate conformations. The results showed that the instantaneous enzyme conformations have two independent consequences on the enzyme’s chemistry: they influence the barrier height, something also observed in the past in other enzymes, but they also influence the specific reaction pathway, which is something unusual and unexpected, challenging the “one enzyme-one substrate-one reaction mechanism” paradigm. Two different reaction mechanisms, with similar reactants probabilities and barrier heights, lead to the same gem-diol intermediate, Subtle nanosecond-timescale rearrangements in the active site hydrogen bonding network were shown to determine which reaction the enzyme follows. We named this phenomenon as chemical disorder. The results make us to realize unexpected mechanistic consequences of conformational diversity in enzymatic reactivity.

Back to tab navigation

Supplementary files

Publication details

The article was received on 25 Mar 2019, accepted on 10 Jun 2019 and first published on 11 Jun 2019


Article type: Edge Article
DOI: 10.1039/C9SC01464K
Chem. Sci., 2019, Accepted Manuscript
  • Open access: Creative Commons BY-NC license
  •   Request permissions

    Conformational Diversity Induces Nanosecond-Timescale Chemical Disorder in the HIV-1 Protease Reaction Pathway

    A. R. Calixto, M. J. J. Ramos and P. A. Fernandes, Chem. Sci., 2019, Accepted Manuscript , DOI: 10.1039/C9SC01464K

    This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

    Reproduced material should be attributed as follows:

    • For reproduction of material from NJC:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the Centre National de la Recherche Scientifique (CNRS) and the RSC.
    • For reproduction of material from PCCP:
      [Original citation] - Published by the PCCP Owner Societies.
    • For reproduction of material from PPS:
      [Original citation] - Published by The Royal Society of Chemistry (RSC) on behalf of the European Society for Photobiology, the European Photochemistry Association, and RSC.
    • For reproduction of material from all other RSC journals:
      [Original citation] - Published by The Royal Society of Chemistry.

    Information about reproducing material from RSC articles with different licences is available on our Permission Requests page.

Search articles by author

Spotlight

Advertisements