uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Conformational diversity induces nanosecond-timescale chemical disorder in the HIV-1 protease reaction pathway
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry. Univ Porto, Dept Quim & Bioquim, UCIBIO REQUIMTE, Fac Ciencias, Rua Campo Alegre S-N, P-4169007 Porto, Portugal. (Kamerlin)
Univ Porto, Dept Quim & Bioquim, UCIBIO REQUIMTE, Fac Ciencias, Rua Campo Alegre S-N, P-4169007 Porto, Portugal.
Univ Porto, Dept Quim & Bioquim, UCIBIO REQUIMTE, Fac Ciencias, Rua Campo Alegre S-N, P-4169007 Porto, Portugal.
2019 (English)In: Chemical Science, ISSN 2041-6520, E-ISSN 2041-6539, Vol. 10, no 30, p. 7212-7221Article in journal (Refereed) Published
Abstract [en]

The role of conformational diversity in enzyme catalysis has been a matter of analysis in recent studies. Pre-organization of the active site has been pointed out as the major source for enzymes' catalytic power. Following 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 macroscopically 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 the 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, and 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 reactant 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 chemical disorder. The results make us realize the unexpected mechanistic consequences of conformational diversity in enzymatic reactivity.

Place, publisher, year, edition, pages
2019. Vol. 10, no 30, p. 7212-7221
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-394274DOI: 10.1039/c9sc01464kISI: 000484202600006OAI: oai:DiVA.org:uu-394274DiVA, id: diva2:1358740
Available from: 2019-10-08 Created: 2019-10-08 Last updated: 2019-10-08Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full text

Authority records BETA

Calixto, Ana Rita

Search in DiVA

By author/editor
Calixto, Ana Rita
By organisation
Biochemistry
In the same journal
Chemical Science
Biochemistry and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 12 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf