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Protein Science (2006), 15:2773-2784. Published by Cold Spring Harbor Laboratory Press. Copyright © 2006 The Protein Society
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Critical assessment of quantum mechanics based energy restraints in protein crystal structure refinement

Ning Yu1,2, Xue Li1,3, Guanglei Cui1,3, Seth A. Hayik1,3, and Kenneth M. Merz, Jr.1,3

1 Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA

(RECEIVED May 13, 2006; FINAL REVISION August 3, 2006; ACCEPTED September 10, 2006)

A critical evaluation of the performance of X-ray refinement protocols using various energy functions is presented using the bovine pancreatic trypsin inhibitor (BPTI) protein. The four potential energy functions we explored include: (1) fully quantum mechanical calculations; (2) one based on an incomplete molecular mechanics (MM) energy function employed in the Crystallography and NMR System (CNS) with empirical parameters developed by Engh and Huber (EH), which lacks electrostatic and attractive van der Waals terms; (3) one based on a complete MM energy function (AMBER ff99 parameter set); and (4) the same as 3, with the addition of a Generalized Born (GB) implicit solvation term. The R, R free, real space R values of the refined structures and deviations from the original experimental structure were used to assess the relative performance. It was found that at 1 Å resolution the physically based energy functions 1, 3, and 4 performed better than energy function 2, which we attribute to the better representation of key interactions, particularly electrostatics. The observed departures from the experimental structure were similar for the refinements with physically based energy functions and were smaller than the structure refined with EH. A test refinement was also performed with the reflections truncated at a high-resolution cutoff of 2.5 Å and with random perturbations introduced into the initial coordinates, which showed that low-resolution refinements with physically based energy functions held the structure closer to the experimental structure solved at 1 Å resolution than the EH-based refinements.

Keywords: quantum mechanics; molecular mechanics; protein structures; X-ray structure refinement; linear-scaling; Generalized Born


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