Modeling of the three-dimensional structure of polypeptides in solution using potential-scaled/hot-solute molecular dynamics.

We present here an efficient and accurate procedure for modeling of the three-dimensional structures of polypeptides in the explicit solvent water based on molecular dynamics calculations. Using the toxic domain analog of heat-stable enterotoxin as a model peptide, we examined the utilities of two molecular dynamics techniques with the system containing the explicit solvent. One is the potential-scaled molecular dynamics that had been designed for effective conformational analyses of biomolecules with the explicit solvent water by partially scaling down the potential energies involved in the solute molecules. The other is the variation of Berendsen's weak coupling method (referred to as "hot-solute" method), in which only the solute of the system is heated to a high temperature while the solvent is kept at a normal temperature. Each method successfully increased the rate of folding of the peptides, and the most effective was a combination of the two methods. Moreover, the final structure obtained via cooling process successfully reproduced the experimentally known structure from the extended amino acid sequence using only the distance restraints representing three disulfide bonds in the peptide. Additional distance restraints derived from some of the NOE cross peaks accelerated the folding of the peptide, but gave almost the same structure as in the case without these additional restraints. Because a similar calculation without the explicit solvent could not reproduce the known structure, it is suggested that the explicit solvent water could play an important role in the modeling. The methods presented here have the potential for accurate modeling even when less experimental information was available.