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A simple and fast free energy scoring function (Fresno) has been developed to predict the binding free energy of peptides to class I major histocompatibility (MHC) proteins. It differs from existing scoring functions mainly by the explicit treatment of ligand desolvation and of unfavorable protein-ligand contacts. Thus, it may be particularly useful in predicting binding affinities from three-dimensional models of protein-ligand complexes. The Fresno function was independently calibrated for two different training sets: (a) five HLA-A0201-peptide structures, which had been determined by X-ray crystallography, and (b) three-dimensional models of 37 H-2K(k)-peptide structures, which had been obtained by knowledge-based homology modeling. For both training sets, a good cross-validated fit to experimental binding free energies was obtained with predictive errors of 3-3.5 kJ/mol. As expected, lipophilic interactions were found to contribute the most to HLA-A0201-peptide interactions, whereas H-bonding predominates in H-2K(k) recognition. Both cross-validated models were afterward used to predict the binding affinity of a test set of 26 peptides to HLA-A0204 (an HLA allele closely related to HLA-A0201) and of a series of 16 peptides to H-2K(k). Predictions were more accurate for HLA-A2-binding peptides as the training set had been built from experimentally determined structures. The average error in predicting the binding free energy of the test peptides was 3.1 kJ/mol. For the homology model-derived equation, the average error in predicting the binding free energy of peptides to K(k) was significantly higher (5.4 kJ/mol) but still very acceptable. The present scoring function is thus able to predict with a good accuracy binding free energies from three-dimensional models, at the condition that the backbone coordinates of the MHC-bound peptide have first been determined with an accuracy of about 1-1.5 A. Furthermore, it may be easily recalibrated for any protein-ligand complex.

Nonlocal density functional calculations have been carried out on the electronic and molecular structures of (C5H5)M(L) (L = CO, PH3; M = Rh, Ir) (a) and M(CO)4 (M = Ru, Os) (b). All systems are found to have a singlet ground state. Optimized geometries are reported for each system on the singlet ground state as well as the first excited triplet state. The coordinatively unsaturated 16-electron species X"M = a,b are usually generated from the 18-electron systems X"MY by photolytic (or in some cases thermal) dissociation of Y. Calculated dissociation energies are presented for Y = CO, PH3, and H2 in the case of X"M = a and for Y = CO and H2 in the case of X"M = b. Complete reaction profiles have been calculated for the oxidative addition of H2 and CH4 to a and b. The addition reactions are found to be more facile for a than for b. It is argued that a is unique as a C-H activating agent in having only empty (7-type d-based orbitals interacting with the incoming C-H bond.Most other mononuclear d8 systems, such as b, have empty as well as occupied cr-type metal-based orbitals, and the latter will impede the addition reaction. It is further argued that the high energy of the HOMO on a aids in the addition of H-H and H-CH3 bonds to Cp(L)M. Calculations are presented on the reaction enthalpies of the H-H and C-H addition processes along with the M-H and M-CH3 bond energies. The 5d elements are found to form stronger bonds than their 4d congeners as a result of relativistic effects as well as better bonding overlaps. Geometry optimizations were carried out on the dihydride and hydrido-alkyl complexes. Approximate transition-state structures are presented for the C-H addition reactions.

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