Program to engineer peptides (PEP) is a build-up approach forligand docking and design with implicit solvation. It requires the knowledge of a seed from which it iteratively grows polymeric ligands consisting of any type of amino acid, i.e., natural and/or nonnatural from a user-defined library. At every growing step, a genetic algorithm is used for conformational optimization of the last added monomer in the rigid binding site. Pruning is performed at every growing step by selecting sequences according to binding energy with electrostatic solvation. PEP is applied to three members of the caspase family of cysteine proteases using Asp at P 1 as seed. The optimal P 4 -P 2 peptide recognition motifs and variants thereof are docked correctly in the active site (backbone root-mean-square deviation < 0.9 Å). Moreover, for each caspase, the P 4 -P 2 sequences of potent aldehyde inhibitors are ranked among the 15 hits with the most favorable PEP energy.

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The antibody M␣2-3 neutralizes the functional, acetylcholine receptor binding activity of its antigen, neurotoxin ␣, and exhibits several other properties in common with the receptor itself. We present here the results of calculations examining the threedimensional structure of the toxin ␣:M␣2-3 complex. The antigen structure, determined by nuclear magnetic resonance spectroscopy, 1 was docked to models of the variable fragment of the antibody combining site 2 by using a method based on surface complementarity and maximization of buried surface area 3,4 while taking into account the possibility of conformational change on complexation. Extensive experimental information on the location of the functional epitope was incorporated into the analysis and used to screen candidate geometries of the complex resulting from the modeling. Eight plausible structures that are in accord with the experimental data were derived. Common structural features of the models are discussed, and residues of the antibody-combining site that are expected to play important roles in complexation are identified. In particular, three epitope residues that, according to mutagenesis experiments, make particularly strong contributions to the binding, interact excentrically and do not make contact with the central loops of the combining site, L3 and H3.

Modelled structures of the acetylcholine receptor-mimicking antibody, Malpha2-3, both free and bound to its antigen, toxin alpha, are assessed in the light of new experimental mutational data from functional mapping of the paratopic region of Malpha2-3. The experimental results are consistent with the previously-predicted structure of the free antibody, and also demonstrate that structural particularities of the Malpha2-3 combining site that were identified in the models play a role in the protein association. The modelled conformations of the hypervariable loops are discussed in the context of recent new data and analyses. The new mutational data allow several previously-considered modelled structures of the complex to be rejected. Two quite similar models now remain.

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