Backgound: Proteins fold to unique three-dimensional structures, but how they achieve this transition and how they maintain their native folds is controversial. Information on the functional form of molecular interactions is required to address these issues. The basic building blocks are the free energies of atom pair interactions in dense protein solvent systems. In a dense medium, entropic effects often dominate over internal energies but free energy estimates are notoriously difficult to obtain. A prominent example is the peptide hydrogen bond (H-bond). It is still unclear to what extent H-bonds contribute to protein folding and stability of native structures.ResultsRadial distribution functions of atom pair interactions are compiled from a database of known protein folds. The functions are transformed to Helmholtz free energies using a recipe from the statistical mechanics of dense interacting systems. In particular we concentrate on the features of the free energy functions of peptide H-bonds. Differences in Helmholtz free energies correspond to the reversible work required or gained when the distance between two particles is changed. Consequently, the functions directly display the energetic features of the respective thermodynamic process, such as H-bond formation or disruption.ConclusionIn the H-bond potential, a high barrier isolates a deep narrow minimum at H-bond contact from large distances, but the free energy difference between H-bond contact and large distances is close to zero. The energy barrier plays an intriguing role in H-bond formation and disruption: both processes require activation energy in the order of 2kT. H-bond formation opposes folding to compact states, but once formed, H-bonds act as molecular locks and a network of such bonds keeps polypeptide chains in a precise spatial configuration. On the other hand, peptide H-bonds do not contribute to the thermodynamic stability of native folds, because the energy balance of H-bond formation is close to zero.

The prediction experiment reveals that fold recognition has become a powerful tool in structural biology. We applied our fold recognition technique to 13 target sequences. In two cases, replication terminating protein and prosequence of subtilisin, the predicted structures are very similar to the experimentally determined folds. For the first time, in a public blind test, the unknown structures of proteins have been predicted ahead of experiment to an accuracy approaching molecular detail. In two other cases the approximate folds have been predicted correctly. According to the assessors there were 12 recognizable folds among the target proteins. In our postprediction analysis we find that in 7 cases our fold recognition technique is successful. In several of the remaining cases the predicted folds have interesting features in common with the experimental results. We present our procedure, discuss the results, and comment on several fundamental and technical problems encountered in fold recognition. © 1995 Wiley‐Liss, Inc.

A major goal in protein structure theory is the development of physical models for protein solvent systems in terms of energy functions or force fields. The successful construction of a reasonable energy model would have an enormous impact on protein science and molecular biology paving the way for a vast number of industrial and scientific applications like the design and production of proteins with improved activity, increased thermostability or desired specificity. In the wake of the genome project the sequences of genes and their protein products are deciphered with an ever increasing rate but in spite of significant progress in experimental structure determination the ratio of known structures to known sequences is still decreasing (Bowie et al. 1991).