X-ray refinement significantly underestimates the level of microscopic heterogeneity in biomolecular crystals

Antonija Kuzmanic, Navraj S. Pannu () and Bojan Zagrovic ()
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Antonija Kuzmanic: Max F. Perutz Laboratories, University of Vienna
Navraj S. Pannu: Biophysical Structural Chemistry, Leiden University
Bojan Zagrovic: Max F. Perutz Laboratories, University of Vienna

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract Biomolecular X-ray structures typically provide a static, time- and ensemble-averaged view of molecular ensembles in crystals. In the absence of rigid-body motions and lattice defects, B-factors are thought to accurately reflect the structural heterogeneity of such ensembles. In order to study the effects of averaging on B-factors, we employ molecular dynamics simulations to controllably manipulate microscopic heterogeneity of a crystal containing 216 copies of villin headpiece. Using average structure factors derived from simulation, we analyse how well this heterogeneity is captured by high-resolution molecular-replacement-based model refinement. We find that both isotropic and anisotropic refined B-factors often significantly deviate from their actual values known from simulation: even at high 1.0 Å resolution and Rfree of 5.9%, B-factors of some well-resolved atoms underestimate their actual values even sixfold. Our results suggest that conformational averaging and inadequate treatment of correlated motion considerably influence estimation of microscopic heterogeneity via B-factors, and invite caution in their interpretation.

Date: 2014
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DOI: 10.1038/ncomms4220

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