Exploring the space of protein folding Hamiltonians:: The balance of forces in a minimalist β-barrel model

A rapid and effective method for obtaining thermodynamic quantities for Hamiltonians whose configurational space has not been examined through a direct simulation has been developed. This approach extends the scope of the weighted histogram analysis method and is applied to the exploration of the balance of forces within the off-lattice Honeycutt-Thirumalai 46-mer beta-barrel model. Specificity is introduced into the long range hydrophobic interactions by scaling back the non-native attractive component of the hydrophobic interactions through a scaling factor lambda (0<lambda<1). Thermodynamic properties for incremental values of lambda are extrapolated from the sampling of the original (lambda=l) Hamiltonian. The results were found to be in good agreement with the thermodynamic signatures obtained by direct simulations. Decreasing the strength of the non-native attractive hydrophobic interactions leads to a more cooperative folding with the folding and collapse temperatures nearly coinciding at lambda=0.0. The free energy surfaces were also seen to become progressively smoother while retaining a pronounced native well. Thus, this methodology may be used in the development, refinement, and exploration of folding for off-lattice protein models. (C) 1998 American Institute of Physics.