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Article

Is Quantum Mechanics Necessary for Predicting Binding Free Energy?

Supporting Info

Ting Zhou, Danzhi Huang* and Amedeo Caflisch*

Department of Biochemistry, University of Z

rich, Winterthurerstrasse 190, CH-8057 Z

rich, Switzerland

J. Med. Chem., 2008, 51 (14), pp 4280–4288

DOI: 10.1021/jm800242q

Publication Date (Web): June 25, 2008

* To whom correspondence should be addressed. (D.H.) Phone: (+41 44) 635 55 21. Fax: (+41 44) 635 68 62. E-mail: huang@bioc.uzh.ch. (A.C.) Phone: (+41 44) 635 55 21. Fax: (+41 44) 635 68 62. E-mail: caflisch@bioc.uzh.ch.

Abstract

To take into account polarization effects, the linear interaction energy model with continuum electrostatic solvation (LIECE) is supplemented by the linear-scaling semiempirical quantum mechanical calculation of the intermolecular electrostatic energy (QMLIECE). QMLIECE and LIECE are compared on three enzymes belonging to different classes: the West Nile virus NS3 serine protease (WNV PR), the aspartic protease of the human immunodeficiency virus (HIV-1 PR), and the human cyclin-dependent kinase 2 (CDK2). QMLIECE is superior for 44 peptidic inhibitors of WNV PR because of the different amount of polarization due to the broad range of formal charges of the inhibitors (from 0 to 3). On the other hand, QMLIECE and LIECE show similar accuracy for 24 peptidic inhibitors of HIV-1 PR (20 neutral and 4 with one formal charge) and for 73 CDK2 inhibitors (all neutral). These results indicate that quantum mechanics is essential when the inhibitor/protein complexes have highly variable charge−charge interactions.

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