HELMHOLTZ FREE-ENERGIES OF ATOM PAIR INTERACTIONS IN PROTEINS

Background: Proteins fold io unique three-dimensional structures, but how they achieve this transition and how they maintain their native fo lds is controversial, Information on the functional form of molecular interactions is required to address these issues, The basic building b locks are the free energies of atom pair interactions in dense protein solvent systems. In a dense medium, entropic effects often dominate o ver internal energies but free energy estimates are notoriously diffic ult to obtain, A prominent example is the peptide hydrogen bond (H-bon d). It is still unclear to what extent H-bonds contribute to protein f olding and stability of native structures. Results: Radial distributio n functions of atom pair interactions are compiled from a database of known protein folds. The functions are transformed to Helmholtz free e nergies using a recipe from the statistical mechanics of dense interac ting systems. In particular we concentrate on the features of the free energy functions of peptide H-bonds. Differences in Helmholtz free en ergies correspond to the reversible work required or gained when the d istance between two particles is changed, Consequently, the functions directly display the energetic features of the respective thermodynami c process, such as H-bond formation or disruption. Conclusions: In the H-bond potential, a high barrier isolates a deep narrow minimum at H- bond contact from large distances, but the free energy difference betw een H-bond contact and large distances is close to zero. The energy ba rrier plays an intriguing role in H-bond formation and disruption: bot h processes require activation energy in the order of 2kT. H-bond form ation opposes folding to compact states, but once formed, H-bonds act as molecular locks and a network of such bonds keeps polypeptide chain s in a precise spatial configuration. On the other hand, peptide H-bon ds do not contribute to the thermodynamic stability of native folds, b ecause the energy balance of H-bond formation is close to zero. (C) Cu rrent Biology Ltd