On the calculation of binding free energies using continuum methods: Application to MHC class I protein‐peptide interactions

• Published in: Protein science 1997-06, Vol.6 (6), p.1293-1301
• Main Authors: Froloff, Nicolas, Windemuth, Andreas, Honig, Barry
• Format: Article
• Language: English
• Subjects: Animals; binding free energy; Computer Simulation; H-2 Antigens - chemistry; H-2 Antigens - metabolism; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - metabolism; HLA-A2 Antigen - chemistry; HLA-A2 Antigen - metabolism; Humans; hydrophobic effect; Major Histocompatibility Complex; Mice; Models, Chemical; Peptides - chemistry; Peptides - metabolism; Poisson Distribution; Poisson‐Boltzmann electrostatics; Protein Binding; protein‐peptide interactions; Sensitivity and Specificity; solvation free energy; Solvents - chemistry; Static Electricity; Thermodynamics; Water - chemistry
• ISSN: 0961-8368; 1469-896X
• DOI: 10.1002/pro.5560060617

This paper describes a methodology to calculate the binding free energy (ΔG) of a protein‐ligand complex using a continuum model of the solvent. A formal thermodynamic cycle is used to decompose the binding free energy into electrostatic and non‐electrostatic contributions. In this cycle, the reactants are discharged in water, associated as purely nonpolar entities, and the final complex is then recharged. The total electrostatic free energies of the protein, the ligand, and the complex in water are calculated with the finite difference Poisson‐Boltzmann (FDPB) method. The nonpolar (hydrophobic) binding free energy is calculated using a free energy‐surface area relationship, with a single alkane/water surface tension coefficient (γaw). The loss in backbone and side‐chain configurational entropy upon binding is estimated and added to the electrostatic and the nonpolar components of ΔG. The methodology is applied to the binding of the murine MHC class I protein H‐2Kb with three distinct peptides, and to the human MHC class I protein HLA‐A2 in complex with five different peptides. Despite significant differences in the amino acid sequences of the different peptides, the experimental binding free energy differences (ΔΔGexp) are quite small (