The peptide bond rupture mechanism in the serine proteases: an in silico study based on sequential scale models
dc.contributor.author
dc.date.accessioned
2023-03-28T12:03:07Z
dc.date.available
2023-03-28T12:03:07Z
dc.date.issued
2023-03-14
dc.identifier.issn
1463-9076
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dc.description.abstract
Given the importance of serine proteases for biochemical processes, we have studied the peptide bond rupture mechanism using three sequential scale models as representations of the KLK5 enzyme (a protein overexpressed in ovarian cancer). The first model contains the basic functional groups of the residues that conform the catalytic triad present in serine proteases; the second model consists of considering some additional residues and, finally, the last representation includes all atoms of the KLK5 protein together with 10.000 explicit water molecules. This separation into three scale models allows us to separate the intrinsic reactivity of the catalytic triad from the process taking place in the enzyme. The methodologies employed in this work include full DFT calculations with a dielectric continuum in the first two models and a multi-level setup with a Quantum Mechanics/Molecular Mechanics (QM/MM) partition in the whole protein system. Our results show that the peptide-bond rupture mechanism is a stepwise process involving two proton transfer reactions. The rate-determining step is the second proton transfer from the imidazole group to the amidic nitrogen of the substrate. In addition, we find that the simplest model does not provide accurate results compared to the full protein system. This can be attributed to the electronic stabilization conferred by the residues around the reaction site. Interestingly, the energy profile obtained with the second scale model with additional residues shows the same trends as the full system and could therefore be considered an appropriate model system. It could be used for studying the peptide bond rupture mechanism in case full QM/MM calculations cannot be performed, or as a rapid tool for screening purposes
dc.description.sponsorship
We thank the Laboratorio Nacional de Caracterización de Propiedades Fisicoquímicas y Estructura Molecular (UG-UAA-CONACYT, Project: 123732) for the computing time provided at the PIPILA cluster, AEI/MCIU (projects PID2020-114548GB-I00 and PID2020-113711GB-I00), the Generalitat de Catalunya (projects 2021SGR00623 and 2021SGR00487), and FEDER (UNGI10-4E-801) for financial support
Open Access funding provided thanks to the CSUC agreement with Royal Society of Chemistry (RSC)
dc.format.extent
7 p.
dc.format.mimetype
application/pdf
dc.language.iso
eng
dc.publisher
Royal Society of Chemistry (RSC)
dc.relation
PID2020-113711GB-I00
PID2020-114548GB-I00
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Versió postprint del document publicat a: https://doi.org/10.1039/D2CP04872H
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© Physical Chemistry Chemical Physics, 2023, vol. 25, p. 8043-8049
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Articles publicats (D-Q)
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Tots els drets reservats
dc.source
Díaz Cervantes, Erik Robles, Juvencio Solà i Puig, Miquel Swart, Marcel 2023 The peptide bond rupture mechanism in the serine proteases: an in silico study based on sequential scale models Physical Chemistry Chemical Physics 25 8043 8049
dc.subject
dc.title
The peptide bond rupture mechanism in the serine proteases: an in silico study based on sequential scale models
dc.type
info:eu-repo/semantics/article
dc.rights.accessRights
info:eu-repo/semantics/openAccess
dc.embargo.lift
2024-03-14T00:00:00Z
dc.embargo.terms
2024-03-14T00:00:00Z
dc.date.embargoEndDate
info:eu-repo/date/embargoEnd/2024-03-14
dc.relation.projectID
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-113711GB-I00/ES/DISEÑO Y SINTESIS DE FULLERENOS PARA LA CONSTRUCCION DE CELDAS SOLARES HIBRIDAS DE PEROVSKITA Y FULERENOS D ALTO RENDIMIENTO. UN ENFOQUE EXPERIMENTAL Y COMPUTACIONAL SINERGICO/
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-114548GB-I00/ES/CORRELATING FUNCTIONALITY/
dc.type.version
info:eu-repo/semantics/acceptedVersion
dc.identifier.doi
dc.identifier.idgrec
036786
dc.contributor.funder
dc.type.peerreviewed
peer-reviewed
dc.relation.FundingProgramme
dc.relation.ProjectAcronym
dc.identifier.eissn
1463-9084