FLEXIBLE DOCKING OF PEPTIDES TO CLASS-I MAJOR-HISTOCOMPATIBILITY-COMPLEX RECEPTORS

We present a new method for docking flexible peptides to class I Major -Histocompatibility-Comp]ex (MHC) receptors. Docking is performed in t wo steps: (a) The charged terminal peptide residues are located by ran domly distributing multiple copies of each in volumes of approximate t o 150 Angstrom(3) at either end of the binding groove, and then minimi zing the system energy using a modified multiple-copy search algorithm . This is followed by (b) construction of the intervening chain using the multiple-copy bond-scaling-relaxation loop closure algorithm. In b oth steps, the copies tend to cluster and the size of the resulting cl usters is proportional to the basin of attraction of the corresponding energy well. We show that native MHC-bound peptides have broad minima and, consequently, that misfolded, low-energy peptide conformations c an be eliminated by restricting consideration to groups of peptides wh ich cluster into broad minima. The accuracy of the method is assessed by comparing the predictions with crystallographic data for three diff erent MHC peptide systems, at various degrees of stringency: (a) the e xtent to which we can determine side chain function (anchor vs. T-cell epitopes); (b) the extent to which we can determine the peptide-recep tor orientation; and (c) the accuracy with which we can predict atomic coordinates. We find the method correct on (a) for 19 of the 22 non-G ly positions; the failures appearing to be a consequence of omitting s olvation. Predictions related to (b) are also very encouraging, with t he overall orientation of the predicted peptides being very similar to the crystal conformation, when measured by the hydrogen bonding patte rn between the two. The degree of success in predicting atomic coordin ates varied considerably, however, from 1.4 Angstrom for the HLA-A2 pe ptide to 2.7 Angstrom for the K-b peptide. The inaccuracy of the latte r appears to reflect an incomplete target function, most likely the om mission of solvation. The calculations thus define the current limits of accuracy in hocking flexible peptides to Class I receptors and iden tify the methodological improvements that must be made for the next ad vance in accuracy.