Prediction of Protein Tertiary Structures by Monte Carlo Simulated Annealing and Multicanonical Algorithms

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We have been advocating the use of Monte Carlo simulated annealing and multicanonical algorithms in the protein folding problem. Although we have been testing the algorithms by simulations in gas phase, it is well known that the effects of solvent are very important for the protein structure formation and stability. It is thus very important to develop an efficient method of inclusion of solvent effects in the simulations. We have tested the inclusion of solvent effects in three different models. First one is based on an energy term that is proportional to solvent accessible surface area. The second one is based on an energy term that represents hydrophobic effects by the scaled particle theory. The third one is based on an energy term that represents all the solvent effects by the RISM theory.For the first possiblity, we compared the validity of 5 commonly used parameter sets for the solvent accessible surface area for Met-enkephalin and Protein G.We have shown that two out of the five are inappropriate. For the second possibility that is based on the scaled particle theory, we performed Monte Carlo simulated annealing simulations for Met-enkephalin. We found that the lowest-energy conformation obtained is more extended than that obtained in gas-phase simulations. This is consistent with NMR experiments, Which indicates that Met-enkephalin is fully extended in aqueous solution. Finally, for the case of RISM theory, we calculated the solvation energies of six conformations that we prepared for comparison. We found that a fully extended structure has the lowest total energy among the six. We are now ready for starting serious simulations by Monte Carlo simulated annealing and/or multicanonical algorithms.