Patent ID: 7415361

Claim:
A method for assigning a binding affinity between polypeptide amino acid residues and one or more molecular fragments, comprising: (a) conducting multiple computer simulations of (i) a polypeptide comprised of amino acid residues, and (ii) at least one molecular fragment, wherein a sampling from a thermodynamically relevant ensemble of states between the polypeptide and each molecular fragment is collected, wherein multiple simulations are performed at multiple values of B and binding affinity values between fragments and residues are obtained by observing the chemical potential value at which each fragment leaves the ensemble by changing the chemical potential at constant temperature, and estimating the affinity estimated by B-critical, wherein B-critical is defined as the minimum B value for which a particular fragment is persistently observed in the vicinity of a residue, wherein B is related to the excess chemical potential of the system according to the relation B=μ′/kT+ln<N>, where μ′ is the excess chemical potential, k is the Boltzmann's constant, T is the absolute temperature, and <N> is the average number of molecular fragments in the simulation; (b) assigning a binding affinity value calculated in step (a) to at least one fragment-residue pair when said fragment of said fragment-residue pair has a finite probability to be in the vicinity of the residue of said fragment-residue pair, wherein said affinity value is an estimate of the free energy of binding between the polypeptide amino acid residue and the fragment; and (c) outputting a matrix of binding affinity values assigned in step (b); wherein (a) and (b) are conducted for each molecular fragment considered in the computer simulation; (d) repeating (a), (b) and (c) for a plurality of fragment types, wherein each fragment type belongs to at least one fragment family; (e) averaging the binding affinity values over a plurality of fragment families to yield a matrix of average binding affinity values, wherein the fragment family is selected from the group consisting of polar, aliphatic and heterocyclic, and (f) coding the three dimensional rendering of the polypeptide surface according to the matrix of average binding affinity values.