SYNERGY BETWEEN SIMULATION AND EXPERIMENT IN DESCRIBING THE ENERGY LANDSCAPE OF PROTEIN-FOLDING

Experimental data from protein engineering studies and NMR spectroscop y have been used by theoreticians to develop algorithms for helix prop ensity and to benchmark computer simulations of folding pathways and e nergy landscapes. Molecular dynamic simulations of the unfolding of ch ymotrypsin inhibitor 2 (CI2) have provided detailed structural models of the transition state ensemble for unfolding/folding of the protein. We now have used the simulated transition state structures to design faster folding mutants of CI2, The models pinpoint a number of unfavor able local interactions at the carboxyl terminus of the single alpha-h elis and in the protease-binding loop region of CI2, By removing these interactions or replacing them with stabilizing ones, we have increas ed the rate of folding of the protein up to 40-fold (tau = 0.4 ms). Th is correspondence, and other examples of agreement between experiment and theory in general, Phi-values and molecular dynamics simulations, in particular, suggest that significant progress has been made toward describing complete folding pathways at atomic resolution by combining experiment and simulation.