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 sequence is presented. This multistep procedure initially uses a simplified approach to protein structure prediction, MONSSTER, that assembles structures from initial extended conformations and scores them. Then, using the lowest-energy low-resolution model as a starting conformation, a detailed atomic model is built and refined using molecular dynamics simulations that employ the locally enhanced sampling (LES) methodology with the particle mesh Ewald (PME) technique for calculation of long-range electrostatic interactions. The combined method is applied to a small disulfide-rich 29-residue protein CMTI-1, a trypsin inhibitor found in squash seeds. Starting with an initial low-resolution model from MONSSTER, which has an rmsd from the native conformation of 3.7 Å (5.0 Å) for C_α atoms (all heavy atoms), LES/PME refinement leads to a structure that is only 2.5 Å (3.3 Å) from native, with a C_α rmsd of only 1.7 Å for residues 5-29. These rmsd values should be compared to C_α rmsd values of 1.2 Å (all residues) or 0.8 Å (residues 5-29) found in PME molecular dynamics simulations that start with the native conformation.