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

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 ofmore » more advanced applications such as Amber-based ensemble refinement, quantum-mechanical representation of active sites and improved geometric restraints for simulated annealing.« less

Authors:
ORCiD logo [1];  [2];  [2];  [2]; ORCiD logo [3]; ORCiD logo [2]; ORCiD logo [4]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Rutgers Univ., Piscataway, NJ (United States)
  3. Duke Univ., Durham, NC (United States)
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of California, Berkeley, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Institutes of Health (NIH); Phenix Industrial Consortium
OSTI Identifier:
1599830
Grant/Contract Number:  
[AC02-05CH11231; GM122086; P01GM063210]
Resource Type:
Accepted Manuscript
Journal Name:
Acta Crystallographica. Section D. Structural Biology
Additional Journal Information:
[ Journal Volume: 76; Journal Issue: 1]; Journal ID: ISSN 2059-7983
Publisher:
IUCr
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Amber refinement target; hydrogen-bond quality; Amber in Phenix; Cβ deviations; peptide orientations

Citation Formats

Moriarty, Nigel W., Janowski, Pawel A., Swails, Jason M., Nguyen, Hai, Richardson, Jane S., Case, David A., and Adams, Paul D. Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix. United States: N. p., 2020. Web. doi:10.1107/S2059798319015134.
Moriarty, Nigel W., Janowski, Pawel A., Swails, Jason M., Nguyen, Hai, Richardson, Jane S., Case, David A., & Adams, Paul D. Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix. United States. doi:10.1107/S2059798319015134.
Moriarty, Nigel W., Janowski, Pawel A., Swails, Jason M., Nguyen, Hai, Richardson, Jane S., Case, David A., and Adams, Paul D. Wed . "Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix". United States. doi:10.1107/S2059798319015134. https://www.osti.gov/servlets/purl/1599830.
@article{osti_1599830,
title = {Improved chemistry restraints for crystallographic refinement by integrating the Amber force field into Phenix},
author = {Moriarty, Nigel W. and Janowski, Pawel A. and Swails, Jason M. and Nguyen, Hai and Richardson, Jane S. and Case, David A. and Adams, Paul D.},
abstractNote = {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.},
doi = {10.1107/S2059798319015134},
journal = {Acta Crystallographica. Section D. Structural Biology},
number = [1],
volume = [76],
place = {United States},
year = {2020},
month = {1}
}

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