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Article

Fine-Tuning of Sequence Specificity by Near Attack Conformations in Enzyme-Catalyzed Peptide Hydrolysis

1
Heidelberg Institute for Theoretical Studies, Schloss-Wolfsbrunnenweg 35, 69118 Heidelberg, Germany
2
Infection Biology Unit, Universitat Pompeu Fabra, Carrer Doctor Aiguader 88, Barcelona Biomedical Research Park, 08003 Barcelona, Spain
Catalysts 2020, 10(6), 684; https://doi.org/10.3390/catal10060684
Received: 13 April 2020 / Revised: 31 May 2020 / Accepted: 8 June 2020 / Published: 18 June 2020
(This article belongs to the Special Issue Quantum Chemical Modelling of Enzymatic Reactions)
The catalytic role of near attack conformations (NACs), molecular states that lie on the pathway between the ground state (GS) and transition state (TS) of a chemical reaction, is not understood completely. Using a computational approach that combines Bürgi–Dunitz theory with all-atom molecular dynamics simulations, the role of NACs in catalyzing the first stages of HIV-1 protease peptide hydrolysis was previously investigated using a substrate that represents the recognized SP1-NC cleavage site of the HIV-1 Gag polyprotein. NACs were found to confer no catalytic effect over the uncatalyzed reaction there ( Δ Δ G N 0 kcal/mol). Here, using the same approach, the role of NACs across multiple substrates that each represent a further recognized cleavage site is investigated. Overall rate enhancement varies by | Δ Δ G | 12–15 kcal/mol across this set, and although NACs contribute a small and approximately constant barrier to the uncatalyzed reaction (< Δ G N u > = 4.3 ± 0.3 kcal/mol), they are found to contribute little significant catalytic effect ( | Δ Δ G N | 0–2 kcal/mol). Furthermore, no correlation is exhibited between NAC contributions and the overall energy barrier ( R 2 = 0.01). However, these small differences in catalyzed NAC contributions enable rates to match those required for the kinetic order of processing. Therefore, NACs may offer an alternative and subtle mode compared to non-NAC contributions for fine-tuning reaction rates during complex evolutionary sequence selection processes—in this case across cleavable polyproteins whose constituents exhibit multiple functions during the virus life-cycle. View Full-Text
Keywords: enzyme catalysis; bimolecular reactions; molecular dynamics; HIV-1 protease; near attack conformations; enzyme specificity enzyme catalysis; bimolecular reactions; molecular dynamics; HIV-1 protease; near attack conformations; enzyme specificity
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MDPI and ACS Style

Sadiq, S.K. Fine-Tuning of Sequence Specificity by Near Attack Conformations in Enzyme-Catalyzed Peptide Hydrolysis. Catalysts 2020, 10, 684. https://doi.org/10.3390/catal10060684

AMA Style

Sadiq SK. Fine-Tuning of Sequence Specificity by Near Attack Conformations in Enzyme-Catalyzed Peptide Hydrolysis. Catalysts. 2020; 10(6):684. https://doi.org/10.3390/catal10060684

Chicago/Turabian Style

Sadiq, S. K. 2020. "Fine-Tuning of Sequence Specificity by Near Attack Conformations in Enzyme-Catalyzed Peptide Hydrolysis" Catalysts 10, no. 6: 684. https://doi.org/10.3390/catal10060684

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