Abstract: A method implemented in the form of a computer simulation code for evaluating the free energy of binding between polypeptide amino acid residues and one or more molecular fragment types is presented. The basis of the method is a novel weighted Metropolis Monte Carlo approach for sampling the grand canonical ensemble. By making use of the properties of the grand canonical ensemble, the affinity of fragments for binding in the vicinity of each protein residue can be efficiently computed. The binding volume associated to each fragment-residue pair is estimated on the basis of a simple proximity criteria, and a useful affinity mapping of the protein surface can be obtained in this way. The analysis of such data for various fragment types provides valuable information to help identify protein binding sites, as well as to identify key fragments used for building potential drug leads.

Abstract: Methods and systems for improving virtual representations of large molecules provide a “prepared” virtual representation of the target protein. The prepared virtual representation of the target protein is useful for further in-silico, or computer processing. Further processing can include, without limitation, designing of small molecules that will potentially bind and/or interact with the target protein. In accordance with the invention, one or more features of the virtual representation of the protein are assessed. One or more of a variety of assessments can be performed including, without limitation, analyzing for completeness (e.g., missing and/or incomplete residues and/or side chains), identifying missing (typically smaller) atoms, determining ionization states (i.e., protonated or not), determining orientation of bonds, and/or identifying atoms that are not part of the protein.

Abstract: The effective Born radii of atoms in a molecule are determined using a new molecular modeling technique. In this approach, the electrical polarization component of solvation energy of an atom i is approximated as the electrical polarization energy given by the classical Born equation (Eq. 2), assuming that the Born radius .alpha. is equal to the van der Waals radius of the atom, minus the effects of all surrounding atoms, j, which displace solvent from around atom i. This displacement effect increases with the volume of the atom j and decreases as the fourth power of the separation between atom i and atom j. E.sub.pol for atom i can therefore be calculated using the following equation:E.sub.pol,i =-166(1-1/.epsilon.)q.sub.i [1/(P.sub.0 +R.sub.i)-.SIGMA.PV.sub.j /r.sub.ij.sup.4 ]wherein R.sub.i is the van der Waals radius of atom i, V.sub.j is the volume of an atom j, and P.sub.0 and P are empirically determined, solvent-dependant constants or functions of r.sub.ij, This value of E.sub.