Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix.

Nigel W Moriarty,Pawel A Janowski,Hai Nguyen,Jason M Swails,Paul D Adams,Jane S Richardson,David A Case

doi:10.1107/s2059798319015134

Abstract

The refinement of biomolecular crystallographic models relies on geometric restraints to help to address the paucity of experimental data typical in these experiments. Limitations in these restraints can degrade the quality of the resulting atomic models. Here, an integration of the full all-atom Amber molecular-dynamics force field into Phenix crystallographic refinement is presented, which enables more complete modeling of biomolecular chemistry. The advantages of the force field include a carefully derived set of torsion-angle potentials, an extensive and flexible set of atom types, Lennard-Jones treatment of nonbonded interactions and a full treatment of crystalline electrostatics. The new combined method was tested against conventional geometry restraints for over 22 000 protein structures. Structures refined with the new method show substantially improved model quality. On average, Ramachandran and rotamer scores are somewhat better, clashscores and MolProbity scores are significantly improved, and the modeling of electrostatics leads to structures that exhibit more, and more correct, hydrogen bonds than those refined using traditional geometry restraints. In general it is found that model improvements are greatest at lower resolutions, prompting plans to add the Amber target function to real-space refinement for use in electron cryo-microscopy. This work opens the door to the future development of more advanced applications such as Amber-based ensemble refinement, quantum-mechanical representation of active sites and improved geometric restraints for simulated annealing.

Highlights

Accurate structural knowledge lies at the heart of our understanding of the biomolecular function and interactions of proteins and nucleic acids
The same procedure was used to estimate an optimal weight for the Phenix–Amber refinements. (If faster fixed-weight refinements are desired, we have found that a scaling factor of 0.2, rather than 0.5, scales the Amber gradients to be close to those from the Conformation Dependent Library (CDL)/E&H restraints, allowing the simpler, default, weighting scheme in phenix.refine to be used.)
The increase was less for Rfree than Rwork, such that RÁ is less for refinements using Amber gradients

Summary

Introduction

Accurate structural knowledge lies at the heart of our understanding of the biomolecular function and interactions of proteins and nucleic acids. These restraints, which can be thought of as a prior in the Bayesian sense, provide additional observations in the optimization target and reduce the danger of overfitting. Their use leads to higher quality, more chemically accurate models

Methods

Results

Discussion

Conclusion