Molecular recognition—viewed through the eyes of the solvent.pdfVIP

Biophysical Chemistry 101 – 102 (2002) 309–319 Molecular recognition—viewed through the eyes of the solvent A. Ben-Naim* Department of Physical Chemistry, The Hebrew University, University Plaza, Jerusalem 91904, Israel Abstract The binding of a ligand L to a specific site on an adsorbent molecule P is usually studied within the lock-and-key model. In this article we argue that the presence of an aqueous solvent may change dramatically the means by which a ligand recognizes its binding site. The main factor, originating from the specific property of water, is the ability of a water molecule to form a hydrogen-bond-bridge between a functional group on L and a functional group on P. This factor will change the criterion for selecting the best binding site. ? 2002 Elsevier Science B.V. All rights reserved. Keywords: Functional groups; Gibbs energy; Binding site; Molecular recognition; Hydrophilic interactions 1. Introduction Binding processes are ubiquitous in biological systems w1–4x. These range from binding of small molecules, like drugs to plasma proteins to binding of proteins to DNA. Most of these binding processes are highly specific with respect to the selection of the binding site. How does a given ligand select the specific site, on a relatively large surface of the adsorbent molecule, on which it binds? This is the problem of molecular recognition. Almost all the studies of the means by which a ligand molecule ‘recognizes’ the selected binding site have focussed on the geometry, or the form, of the binding partner. The geometrical fit between the ligand and the binding site lies at the heart of the well known lock-and-key model (Fig. 1a), *Tel.: q972 2651 3742; fax: q972 265 85733. E-mail address: arieh@batata.fh.huji.ac.il (A. Ben-Naim). proposed more than 100 years ago by Emil Fischer (1897) w1–3x. Modern drug-design methodologies are also based on the search for the best geometrical fits between ligands and potential binding sites w5–9x. Indeed, if one as