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Enantioselectivity in Candida antarctica lipase B: A molecular dynamics study
KTH, Superseded Departments, Biotechnology.
KTH, Superseded Departments, Biotechnology.
KTH, Superseded Departments, Biotechnology.
2001 (English)In: Protein Science, ISSN 0961-8368, E-ISSN 1469-896X, Vol. 10, no 2, 329-338 p.Article in journal (Refereed) Published
Abstract [en]

A major problem in predicting the enantioselectivity of an enzyme toward substrate molecules is that even high selectivity toward one substrate enantiomer over the other corresponds to a very small difference in free energy. However, total free energies in enzyme-substrate systems are very large and fluctuate significantly because of general protein motion. Candida antarctica lipase B (CALB), a serine hydrolase, displays enantioselectivity toward secondary alcohols. Here, we present a modeling study where the aim has been to develop a molecular dynamics-based methodology for the prediction of enantioselectivity in CALB. The substrates modeled (seven in total) were 3-methyl-2-butanol with various aliphatic carboxylic acids and also 2-butanol, as well as 3,3-dimethyl-2-butanol with octanoic acid. The tetrahedral reaction intermediate was used as a model of the transition state. Investigative analyses were performed on ensembles of nonminimized structures and focused on the potential energies of a number of subsets within the modeled systems to determine which specific regions are important for the prediction of enantioselectivity. One category of subset was based on atoms that make up the core structural elements of the transition state. We considered that a more favorable energetic conformation of such a subset should relate to a greater likelihood for catalysis to occur, thus reflecting higher selectivity. The results of this study conveyed that the use of this type of subset was viable for the analysis of structural ensembles and yielded good predictions of enantioselectivity.

Place, publisher, year, edition, pages
2001. Vol. 10, no 2, 329-338 p.
Keyword [en]
molecular dynamics, enantioselectivity, enzyme catalysis, transition state, free energy, enzymatic enantioselectivity, kinetic resolutions, pseudomonas-cepacia, secondary alcohols, nucleic-acids, force-field, stereoselectivity, enantiomers, mechanism, proteins
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-20507DOI: 10.1110/ps.33901ISI: 000167926000011PubMedID: 11266619OAI: oai:DiVA.org:kth-20507DiVA: diva2:339202
Note
QC 20100525Available from: 2010-08-10 Created: 2010-08-10 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Molecular modelling - understanding and prediction of enzyme selectivity.
Open this publication in new window or tab >>Molecular modelling - understanding and prediction of enzyme selectivity.
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Molecular modelling strategies for evaluation of enzyme selectivity wereinvestigated with a focus on principles of how molecular interactionscould be evaluated to provide information about selectivity. Althoughmolecular modelling provides tools for evaluation of geometrical andenergy features of molecular systems, no general strategies for evaluationof enzyme selectivity exist. Geometrical analyses can be based uponinspection and reasoning about molecular interactions, which provide aneasily accessible way to gain information, but suffer from the risk of biasput in by the modeller. They can also be based on geometrical features ofmolecular interactions such as bond lengths and hydrogen-bond formation.Energy analyses are appealing for their modeller independenceand for the possibility to predict not only stereopreference, but also itsmagnitude.In this thesis, four examples of enantio- or regioselective serinehydrolase-catalysed reaction systems are presented together with developedmodelling protocols for explanation, prediction or enhancement ofselectivity. Geometrical as well as energy-based methodology were used,and provided an understanding of the structural basis of enzymeselectivity. In total, the protocols were successful in making qualitative explanationsand predictions of stereoselectivity, although quantitative determinationswere not achieved.

Place, publisher, year, edition, pages
Stockholm: KTH, 2009. 27 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2009:11
Keyword
molecular modelling; regioselectivity; enantioselectivity; molecular dynamics; serine hydrolase; stereospecificity
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-10532 (URN)978-91-7415-325-5 (ISBN)
Presentation
(English)
Supervisors
Available from: 2009-05-26 Created: 2009-05-25 Last updated: 2010-10-12Bibliographically approved

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