SIMULATIONS OF THE FOLDING PATHWAY OF TRIOSE PHOSPHATE ISOMERASE-TYPE-ALPHA BETA BARREL PROTEINS/

Simulations of the folding pathways of two large alpha/beta-proteins, the alpha-subunit of tryptophan synthase and triose phosphate isomeras e, are reported using the knight's walk lattice model of globular prot eins and Monte Carlo dynamics. Starting from randomly generated unfold ed states and with no assumptions regarding the nature of the folding intermediates, for the tryptophan synthase subunit these simulations p redict, in agreement with experiment, the existence and location of a stable equilibrium intermediate comprised of six beta-strands on the a mino terminus of the molecule. For the case of triose phosphate isomer ase, the simulations predict that both amino- and carboxyl-terminal in termediates should be observed. In a significant modification of previ ous lattice models, this model includes a full heavy atom side chain d escription and is capable of representing native conformations at the level of 2.5- to 3-angstrom rms deviation for the C-alpha positions, a s compared to the crystal structure. With a well-balanced compromise b etween accuracy of the protein description and the computer requiremen ts necessary to perform simulations spanning biologically significant amounts of time, the lattice model described here brings the possibili ty of studying important biological processes to present-day computers .