BIOINFORMATICS<-->STRUCTURE
Jerusalem, Israel, November 17-21, 1996

Abstract


Free energy of atom pair interactions in protein folding and structure prediction

Sippl,M.J., Ortner,M., Jaritz,M., Lackner, P. Domingues,F., Flockner,H.

Center of Applied Molecular Engineering, University of Salzburg Jakob Haringer Str.1, A-5020 Salzburg, Austria, Europe.
http://lore.came.sbg.ac.at

sippl@Olga.came.sbg.ac.at


The Brookhaven data bank contains an large number of experimentally determined protein folds. The questions of how and why these proteins adopt unique structures and how they maintain their native folds are controversial issues. In partricular, the role of H-bonds in protein folding seems paradoxical. In vacuo, formation of H-bonds is driven by strong electrostatic forces, but in solution water molecules compete with protein H-bond donors and acceptors. It is still unclear whether the net effect of H-bond formation stabilizes or destabilizes protein folds.

The important physical quantity is the free energy of atom pair interactions, also called potential of mean force. The functional form and relative strength of these potentials can be derived from the structures in the Brookhaven data base. The potentials obtained for interactions involving peptide H-bond donors and acceptors indicate that H-bonds act as molecular locks.

A large free energy barrier separates a deep narrow minimum at H-bond contact from large distances. The barrier plays an intriguing role in H-bond formation and disruption: both processes require activation energy in the order of $2kT$, but the free energy balance of H-bond formation seems to be close to zero. This has important consequences: H-bond formation opposes folding to compact states, but once formed H-bonds act as kinetic traps and a network of such bonds keeps polypeptide chains in a precise spatial configuration. However, peptide H-bonds do not contribute to the thermodynamic stability of protein folds.

(1) Sippl,M.J., Helmholtz free energy of peptide hydrogen bonds in proteins. J.Mol.Biol. (1996), 260, (5), 644-648.
(2) Sippl,M.J., et al., Helmholtz free energy of atom pair interactions in proteins. Folding & Design, (1996) 1, (4), 289-298.
(3) Fl\"ockner,H., et al., Progress in fold recognition. Proteins, 5, 376-386 (1995)
(4) Sippl,M.J., Recognition of Errors in Three-Dimensional Structures of Proteins. Proteins, 17, 355-362 (1993)
(5) Sippl,M.J., The Calculation of Conformational Ensembles from Potentials of Mean Force. J.Mol.Biol., 213, 859-883 (1990)


Back to the Invited Speakers Index.