Transition state docking : a probe for noncovalent catalysis in biological systems. Application to antibody-catalyzed ester hydrolysis
A strategy for pinpointing favorable noncovalent interactions between transition states and active sites of biological catalysts is described. This strategy combines high-level quantum mechanical calculations of transition state geometries with an automated docking procedure using AutoDock. By apply...
| Veröffentlicht in: | Journal of computational chemistry. - 1984. - 23(2002), 1 vom: 15. Jan., Seite 84-95 |
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| Format: | Aufsatz |
| Sprache: | English |
| Veröffentlicht: |
2002
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| Zugriff auf das übergeordnete Werk: | Journal of computational chemistry |
| Schlagworte: | Comparative Study Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S. Amino Acids Antibodies, Catalytic Benzene Derivatives Esters Haptens Organophosphonates mehr... |
| Zusammenfassung: | A strategy for pinpointing favorable noncovalent interactions between transition states and active sites of biological catalysts is described. This strategy combines high-level quantum mechanical calculations of transition state geometries with an automated docking procedure using AutoDock. By applying this methodology to antibody-catalyzed hydrolyses of aryl esters (by the 48G7, CNJ206, and 17E8 families of antibodies), varying levels of catalysis are explained in terms of specific hydrogen bonding interactions between combining site residues and transition states. Although these families of antibodies were produced in separate experiments by different researchers using related but different haptens, the mechanism of transition state stabilization appears to be highly conserved. Despite being elicited in response to anionic phosphonate haptens, the best catalysts often utilize hydrogen bond acceptors to stabilize transition states. A mutant of antibody CNJ206, designed based on this observation and predicted to be a better catalyst, is proposed. In the case of antibody 48G7, affinity maturation is shown to produce a catalyst that is highly selective for one of two enantiomeric transition states from a nonselective germline precursor |
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| Beschreibung: | Date Completed 22.05.2002 Date Revised 21.11.2013 published: Print Citation Status MEDLINE |
| ISSN: | 1096-987X |