Energy- and density- guided refinement for solving difficult molecular replacement problems: Aside from low-resolution data, another challenge in crystal structure determination is known as the phase problem. The problem arises because diffraction of a protein crystal only provides half of the information needed to solve a crystal structure; the other half (the phases) have to be determined experimentally or estimated computationally. The method for the latter is known as molecular replacement, and uses a previously solved structure to estimate the missing phase information. As expected, the approach becomes more difficult the more different this known structure is from the target structure. IPD researchers have developed an approach using energy- and density-guided conformational sampling and refinement in order to solve difficult molecular replacement cases (1,2). This approach has led to the solution of over a dozen structures unsolvable by traditional methods.
1. F. DiMaio, T. Terwilliger, R. Read, A. Wlodawer, G. Oberdorfer, E. Valkov, A. Alon, D. Fass, H. Axelrod, D. Das, S. Vorobiev, H. Iwai, P. Pokkuluri and D. Baker (2011). Improving molecular replacement by density- and energy- guided protein structure optimization. Nature. 473:540-3.
2. F. DiMaio (2013). Advances in Rosetta structure prediction for difficult molecular-replacement problems. Acta Crystallogr D. 69: 2202-8.