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161 Protein folding: the free energy surface Martin Gruebele Quantitative models and experiments are revealing how the configurational entropy, Sc) near the center of the coordinate folding free energy surface of a protein is sculpted by system. The funnel really involves hundreds to thousands sequence and environment. The sometimes conflicting of local backbone and sidechain coordinates. The funnel demands of folding, structure and function determine which postulate posits that, on average, the more compact a protein, folding pathways, if any, dominate. Recent advances include the lower its contact energy (Ec) because of favorable experimental estimates of diffusive barrier-crossing times, the contacts [2]. As shown in Figure 1, the funnel is roughened observation of ultrafast folders amenable to full-atom by effects such as steric hindrance (higher Ec than no contact) simulation, the use of thermodynamic tuning and and non-native contacts (lower Ec than no contact). Strictly nonconservative mutations to probe ‘hidden’ parts of the free speaking, the funnel should also include solvent coordinates, energy surface, and a complete microscopic theory of folding. which interact with the protein in nontrivial ways [9]. In many models, solvent–protein interactions are not Addresses taken into account explicitly, but rather by ‘renormalizing’ Department of Chemistry, Department of Physics, and Center for the protein–protein int