New methods for low-resolution crystallographic refinement

While determination of X-ray crystal structures at moderate to high resolutions has recently accelerated, structure determination and refinement at lower resolutions remains problematic despite considerable recent work. By combining combining the strengths of the Rosetta structure modeling methodology and the Phenix X-ray refinement software, we see significant improvements in refinement at low resolution. Rosetta's all-atom force field compensates for the lack of high-resolution data, while search procedures combining backbone minimization with discrete side-chain optimization more effectively explore alternative side-chain arrangements than simulated annealing.

Our manuscript describes how we incorporate the maximum-likelihood reciprocal-space X-ray target function from phenix.refine into Rosetta. On a set of "realistically" difficult low-resolution cases, our method yielded improved model geometry and lower free R factors than alternate refinement methods. In contrast to reference structure–based restraints, the Rosetta force field makes it possible to discover new energetically favorable interactions — not present in the reference model — during a refinement trajectory.