Redesigning the hydrophobic core of a model beta-sheet protein: Destabilizing traps through a threading approach

An off-lattice 46-bead model of a small all-beta protein has been recently criticized for possessing too many traps and long-lived intermediates compa red with the folding energy landscape predicted for real proteins and model s using the principle of minimal frustration. Using a novel sequence design approach based on threading for finding beneficial mutations for destabili zing traps, we proposed three new sequences for folding in the beta-sheet m odel. Simulated annealing on these sequences found the global minimum more reliably, indicative of a smoother energy landscape, and simulated thermody namic variables found evidence for a more cooperative collapse transition, lowering of the collapse temperature, and higher folding temperatures. Fold ing and unfolding kinetics were acquired by calculating first-passage times , and the new sequences were found to fold significantly faster than the or iginal sequence, with a concomitant lowering of the glass temperature, alth ough none of the sequences have highly stable native structures. The new se quences found here are more representative of real proteins and are good fo lders in the T-f > T-g sense, and they should prove useful in future studie s of the details of transition states and the nature of folding intermediat es in the context of simplified folding models. These results show that our sequence design approach using threading can improve models possessing gla sslike folding dynamics. Proteins 1999;37:582-591. Published 1999 Wiley-Lis s, Inc.dagger