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Computational design of an amidase by combining the best electrostatic features of two promiscuous hydrolases
dc.contributor.author | Galmes, Miquel Angel | |
dc.contributor.author | Nödling, Alexander | |
dc.contributor.author | He, Kaining | |
dc.contributor.author | Luk, Louis Yu Pan | |
dc.contributor.author | Świderek, Katarzyna | |
dc.contributor.author | Moliner, Vicent | |
dc.date.accessioned | 2022-09-19T12:06:41Z | |
dc.date.available | 2022-09-19T12:06:41Z | |
dc.date.issued | 2022-03-15 | |
dc.identifier.citation | GALMÉS, Miquel À., et al. Computational design of an amidase by combining the best electrostatic features of two promiscuous hydrolases. Chemical Science, 2022, vol. 13, no 17, p. 4779-4787. | ca_CA |
dc.identifier.uri | http://hdl.handle.net/10234/199644 | |
dc.description.abstract | While there has been emerging interest in designing new enzymes to solve practical challenges, computer-based options to redesign catalytically active proteins are rather limited. Here, a rational QM/MM molecular dynamics strategy based on combining the best electrostatic properties of enzymes with activity in a common reaction is presented. The computational protocol has been applied to the re-design of the protein scaffold of an existing promiscuous esterase from Bacillus subtilis Bs2 to enhance its secondary amidase activity. After the alignment of Bs2 with a non-homologous amidase Candida antarctica lipase B (CALB) within rotation quaternions, a relevant spatial aspartate residue of the latter was transferred to the former as a means to favor the electrostatics of transition state formation, where a clear separation of charges takes place. Deep computational insights, however, revealed a significant conformational change caused by the amino acid replacement, provoking a shift in the pKa of the inserted aspartate and counteracting the anticipated catalytic effect. This prediction was experimentally confirmed with a 1.3-fold increase in activity. The good agreement between theoretical and experimental results, as well as the linear correlation between the electrostatic properties and the activation energy barriers, suggest that the presented computational-based investigation can transform in an enzyme engineering approach. | ca_CA |
dc.format.extent | 10 p. | ca_CA |
dc.format.mimetype | application/pdf | ca_CA |
dc.language.iso | eng | ca_CA |
dc.publisher | The Royal Society of Chemistry | ca_CA |
dc.relation.isPartOf | Chem. Sci., 2022,13 | ca_CA |
dc.rights | © 2022 The Author(s). Published by the Royal Society of Chemistry | ca_CA |
dc.rights.uri | http://creativecommons.org/licenses/by-nc/4.0/ | ca_CA |
dc.subject | Activation energy | ca_CA |
dc.subject | Bacteriology | ca_CA |
dc.subject | Enzymes | ca_CA |
dc.subject | Mathematical transformations | ca_CA |
dc.subject | Molecular dynamics | ca_CA |
dc.subject | Reaction kinetics | ca_CA |
dc.subject | Scaffolds | ca_CA |
dc.subject | Amidase | ca_CA |
dc.title | Computational design of an amidase by combining the best electrostatic features of two promiscuous hydrolases | ca_CA |
dc.type | info:eu-repo/semantics/article | ca_CA |
dc.identifier.doi | DOI https://doi.org/10.1039/D2SC00778A | |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | ca_CA |
dc.type.version | info:eu-repo/semantics/publishedVersion | ca_CA |
project.funder.name | Ministerio de Ciencia, Innovación y Universidades (Spain) | ca_CA |
project.funder.name | Generalitat Valenciana | ca_CA |
project.funder.name | Universitat Jaume I | ca_CA |
project.funder.name | Cardiff University | ca_CA |
project.funder.name | BBSRC | ca_CA |
project.funder.name | Leverhulme Trust | ca_CA |
project.funder.name | Royal Society of Chemistry | ca_CA |
oaire.awardNumber | PGC2018-094852-B-C21 | ca_CA |
oaire.awardNumber | PID2019-107098RJ-I00 | ca_CA |
oaire.awardNumber | AICO/2019/195 | ca_CA |
oaire.awardNumber | SEJI/2020/007 | ca_CA |
oaire.awardNumber | UJI-A2019-04 | ca_CA |
oaire.awardNumber | UJI-B2020-03 | ca_CA |
oaire.awardNumber | BB/T015799/1 | ca_CA |
oaire.awardNumber | RPG-2017-195 | ca_CA |
oaire.awardNumber | RG170187 | ca_CA |
oaire.awardNumber | RYC2020-030596-I | ca_CA |
oaire.awardNumber | PREDOC/2017/23 | ca_CA |
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