Protein Structure Determination by Molecular Replacement using High-Accuracy Protein Structure Modeling

Abstract

Molecular replacement (MR) technique is to solve the phase problem in x-ray crystallography. Currently, many computational methods are available and they can provide MR solutions when a suitable 3D model of the target molecule is available. In practice, the success of the MR method is limited by various factors including unavailability of suitable 3D models and the ambiguity of crystallographic parameters. Accurate 3D modeling of the target molecule can provide a breakthrough in these cases. Recently, we have developed a protein 3D modeling method which can provide accurate protein 3D models both in backbones and side-chains. In addition, the method provides a variety of protein 3D models with structural variation. In recent blind tests, CASP7 and CASP8 experiments, the method produced the very top quality protein 3D models for high-accuracy template-based modeling targets. We combined this modeling method with a MR technique and successfully determined two protein structures, which could not be determined using conventional methods with available protein templates. It appears that high-accuracy protein 3D modeling for backbones as well as side-chains can boost up the success rate of molecular replacement technique allowing us to solve the phase problem in x-ray crystallography without requiring additional experiments with high cost efforts.