Combining MONSSTER and LES/PME to predict protein structure from amino acid sequence: Application to the small protein CMTI-1

A combined method for the prediction of protein tertiary structures from se quence is presented. This multistep procedure initially uses a simplified a pproach to protein structure prediction, MONSSTER, that assembles structure s from initial extended conformations and scares them. Then, using the lowe st-energy low-resolution model as a starting conformation, a detailed atomi c model is built and refined using molecular dynamics simulations that empl oy the locally enhanced sampling (LES) methodology with the particle mesh E wald (PME) technique for calculation of long-range electrostatic interactio ns. The combined method is applied to a small disulfide-rich 29-residue pro tein CMTI-1, a trypsin inhibitor found in squash seeds. Starting with an in itial low-resolution model from MONSSTER, which has an rmsd from the native conformation of 3.7 Angstrom (5.0 Angstrom) for C-alpha atoms (all heavy a toms), LES/PME refinement leads to a structure that is only 2.5 Angstrom (3 .3 Angstrom) from native, with a C-alpha rmsd of only 1.7 Angstrom for resi dues 5-29. These rmsd values should be compared to C-alpha rmsd values of 1 .2 Angstrom (all residues) or 0.8 Angstrom (residues 5-29) found in PME mol ecular dynamics simulations that start with the native conformation.