Prediction of protein structure by simulating coarse-grained folding pathways: A preliminary report

A set of software tools designed to study protein structure and kinetics has been developed. The core of these tools is a program called Folding Machine (FM) which is able to generate low resolution folding pathways using modest computational resources. The FM is based on a coarse-grained kinetic ab initio Monte-Carlo sampler that can optionally use information extracted from secondary structure prediction servers or from fragment libraries of local structure. The model underpinning this algorithm contains two novel elements: (a) the conformational space is discretized using the Ramachandran basins defined in the local phi-psi energy maps; and (b) the solvent is treated implicitly by rescaling the pairwise terms of the non-bonded energy function according to the local solvent environments. The purpose of this hybrid ab initio/knowledge-based approach is threefold: to cover the long time 'scales of folding, to generate useful 3-dimensional models of protein structures, and, to gain insight on the protein folding kinetics. Even though the algorithm is not yet fully developed, it has been used in a recent blind test of protein structure prediction (CASP5). The FM generated models within 6 Angstrom backbone rmsd for fragments of about 60-70 residues of alpha-helical proteins. For a CASP5 target that turned out to be natively unfolded, the trajectory obtained for this sequence uniquely failed to converge. Also, a new measure to evaluate structure predictions is presented and used along the standard CASP assessment methods. Finally, recent improvements in the prediction of beta-sheet structures are briefly described.