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Document Page 544 interactions between the group replicas are omitted. The polar-hydrogen approximation (PARAM19) of the CHARMM force field is used [27]. In the application of the MCSS method to the sialic acid binding site of the influenza coat protein hemagglutinin [21], HIV-1 aspartic proteinase [22], and thrombin [20,28] the protein was kept fixed; hence, the forces on each replica consist of its internal forces and those due to the protein, which has unique conformation and, therefore, generates a unique field. The positions are compared every 1000 steps to eliminate replicas converging toward a common minimum. Further details concerning the methodology are given in References 21 and 22, while a critical assessment has been presented in Reference 20. B. Simple Approximations of Solvation Effects In previous applications of MCSS [21,22] the effects of the solvent were neglected, i.e., all proteinfragment interactions were calculated with a vacuum potential [27]. This choice was based on the principle that fast methods are necessary to perform effective searches of the binding site and that good candidate ligands subsequently can be ranked in terms of their binding free energy [20,28]. A possible difficulty with this approach is that minimized positions may be missed or misplaced due to the lack of a solvation correction during the MCSS minimization. Electrostatic Shielding In MCSS studies of thrombin [20,28], it was observed that minima of charged groups tend to cluster in the vicinity of charged side chains on the thrombin surface and in the S1 (basic groups) or S1' pocket (acidic groups). It is then necessary to estimate the electrostatic desolvation of both protein and fragment to obtain a realistic ranking of the minima [28]. As a simple test of the importance of electrostatic shielding, a distance-dependent dielectric function [29] was introduced instead of the unit dielectric constant in the vacuum potential. The overall shape of the acetate map did not change, but three more minima were found close to the Lys60F side chain in S1' [20]. It is difficult to find a physical meaning in favor of the distance-dependent dielectric function. Nevertheless, it is a simple and useful approximation, since it yields a smoother and more realistic potential surface than the vacuum Coulombic interaction. Hydrophobic Effect Aliphatic and aromatic fragments do not bear any partial charges in the polar-hydrogen approximation. Hence, MCSS determines their optimal position in the http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_544.html [4/9/2004 12:51:24 AM]
Document Page 545 protein binding site exclusively by van der Waals interactions. Minima of nonpolar fragments may be found in hydrophilic pockets because of the lack of an energy penalty for protein desolvation. A representative example of a cluster of propane minima in a mainly hydrophilic region of the HIV-1 aspartic proteinase binding site is shown in Reference 20. In a simple attempt to approximate desolvation of polar regions of the protein, the attractive contribution of the van der Waals interaction energy was switched off between atoms of nonpolar MCSS fragments and all protein polar hydrogen, nitrogen, oxygen, and sp 2 carbon atoms. In addition, the van der Waals radius of nitrogen and oxygen atoms was increased from the PARAM19 default value of 1.6 Å to 2.2 Å and the van der Waals radius of the aliphatic carbons was reduced by 0.1 Å to avoid the too large van der Waals distance between carbons often produced by PARAM19. The modified force field yields thrombin functionality maps of propane, cyclopentane, cyclohexane, and benzene in agreement with structural data of known inhibitors (see Section II. C). In addition, these nonpolar groups are prevented from occupying hydrophilic pockets. As a further test of the modified force field, the MCSS procedure was used to generate the propane functionality map on the surface of the A peptide chain of the leucine zipper, i.e., residues 249–281 from the yeast transcriptional activator protein GCN4. Leucine zippers are composed of amphipathic α helices containing heptad repeats (abcdefg) in which hydrophobic residues are frequent at a and d. As the x-ray structure indicates [30,31], the two amphipathic α helices are held together by hydrophobic interactions between residues in the a and d positions (Figure 2). The B peptide chain was removed and MCSS was run separately with the original and the modified force field starting from the same random distribution of 5000 propane replicas around helix A. The sixty most favorable minima obtained with the modified force field are distributed in twelve clusters, seven of which match the Val and Leu side chains of the B helix involved in the interhelical interactions (Figure 2). Of the remaining five clusters, labeled A to E in Figure 2, B has minima in contact with Val and Ala side chains, D with Leu and Tyr side chains, while A, C, and E with both a Val or Leu side chain and the alkyl part of Lys side chain. The sixty most favorable minima obtained with the original force field form sixteen clusters (not shown). Only four of these match Val and Leu side chains of the B helix, while eight clusters desolvate one (or more) polar group on the hydrophilic (exposed) surface of the A helix. The functionality maps of polar groups generated with a distance-dependent dielectric and those of nonpolar groups obtained with the modified force field are closer to those obtained by using a continuum dielectric model [32–35] to postprocess the MCSS minima and estimate solvation effects [28]. Hence, simple modifications of the force field may result in more accurate projections of the binding free energy. Since these modifications are used during the http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_545.html [4/9/2004 12:51:27 AM]
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Document [Interleukin-1] homology w
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Document Kininogen, 119 high molecu
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Document Matrix-metalloproteinase (
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Document RT inhibitor, 41, 56 Nonpe
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Document Phosphoglycerate kinase (P
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Document [Protease targets] serinyl
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