Transition state docking: a probe for noncovalent catalysis in biological systems. Application to antibody-catalyzed ester hydrolysis

Journal of Computational Chemistry
D J Tantillo, K N Houk

Abstract

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 pre...Continue Reading

References

Jul 1, 1992·Biological Chemistry Hoppe-Seyler·R Ménard, A C Storer
Oct 8, 1991·Biochemistry·M T MartinA R Rees
Jan 1, 1990·Proteins·D S Goodsell, A J Olson
Sep 29, 1995·Science·P G Schultz, R A Lerner
Feb 28, 1995·Proceedings of the National Academy of Sciences of the United States of America·J GuoT S Scanlan
Jun 21, 1994·Proceedings of the National Academy of Sciences of the United States of America·H MiyashitaI Fujii
Mar 15, 1994·Structure·B Golinelli-PimpaneauM Knossow
Feb 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·S A LesleyP G Schultz
Jan 21, 1994·Journal of Molecular Biology·V A RobertsE D Getzoff
Feb 23, 1996·Science·P A PattenP G Schultz
Jan 1, 1996·Journal of Molecular Recognition : JMR·D S GoodsellA J Olson
Jun 1, 1996·Chemistry & Biology·G MacBeath, D Hilvert
Aug 1, 1996·Journal of Computer-aided Molecular Design·G M MorrisA J Olson
Aug 1, 1996·Journal of Computer-aided Molecular Design·C A SotrifferJ M Varga
Mar 1, 1996·Acta Chemica Scandinavica·A J Kirby
Dec 1, 1996·Natural Product Reports·N R Thomas
Mar 1, 1997·Bioorganic & Medicinal Chemistry·G P MillerS J Benkovic
May 2, 1997·Journal of Molecular Biology·G J WedemayerR C Stevens
Jun 13, 1997·Science·G J WedemayerR C Stevens
Jun 1, 1997·European Journal of Biochemistry·B GigantM Knossow
Aug 1, 1997·Current Opinion in Biotechnology·D B Smithrud, S J Benkovic
Sep 18, 1997·Proceedings of the National Academy of Sciences of the United States of America·M BacaJ A Wells
Jul 25, 1998·The Journal of Biological Chemistry·A OrdentlichA Shafferman
Oct 1, 1998·Journal of Molecular Biology·J L BuchbinderR J Fletterick
Aug 10, 1999·Journal of Molecular Biology·M M ThayerV A Roberts
Mar 15, 1999·Angewandte Chemie·Andrew M Davis, Simon J Teague

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Citations

Jul 3, 2007·Nature·Johannes C HermannFrank M Raushel
Jul 18, 2003·Journal of Computational Chemistry·Lillian T ChongPeter A Kollman
Nov 30, 2012·Angewandte Chemie·Katrien Brak, Eric N Jacobsen
Jan 9, 2008·The Journal of Organic Chemistry·Xiyun ZhangK N Houk
Nov 15, 2019·The Journal of Physical Chemistry. a·Hui Yang, Ming Wah Wong
Mar 29, 2003·The Journal of Organic Chemistry·Samuël P de VisserSason Shaik

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