Quantitative Assessment of Protein Structural Models by Comparison of H/D Exchange MS Data with Exchange Behavior Accurately Predicted by DXCOREX |
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Authors: | Tong Liu Dennis Pantazatos Sheng Li Yoshitomo Hamuro Vincent J Hilser Jr" target="_blank">Virgil L WoodsJr |
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Institution: | (1) Department of Medicine and Biomedical Sciences Graduate Program, University of California, 9500 Gilman Drive, mc 0656, La Jolla, San Diego, CA 92093, USA;(2) Rhode Island Hospital Proteomics Core, COBRE Center for Cancer Research and Development, The Warren Alpert Medical School of Brown University, The Coro Center, Providence, RI, USA;(3) ExSAR Corporation, Monmouth Junction, NJ, USA;(4) Department of Biology, Johns Hopkins University, Baltimore, MD, USA; |
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Abstract: | Peptide amide hydrogen/deuterium exchange mass spectrometry (DXMS) data are often used to qualitatively support models for
protein structure. We have developed and validated a method (DXCOREX) by which exchange data can be used to quantitatively
assess the accuracy of three-dimensional (3-D) models of protein structure. The method utilizes the COREX algorithm to predict
a protein’s amide hydrogen exchange rates by reference to a hypothesized structure, and these values are used to generate
a virtual data set (deuteron incorporation per peptide) that can be quantitatively compared with the deuteration level of
the peptide probes measured by hydrogen exchange experimentation. The accuracy of DXCOREX was established in studies performed
with 13 proteins for which both high-resolution structures and experimental data were available. The DXCOREX-calculated and
experimental data for each protein was highly correlated. We then employed correlation analysis of DXCOREX-calculated versus
DXMS experimental data to assess the accuracy of a recently proposed structural model for the catalytic domain of a Ca2+-independent phospholipase A2. The model’s calculated exchange behavior was highly correlated with the experimental exchange results available for the
protein, supporting the accuracy of the proposed model. This method of analysis will substantially increase the precision
with which experimental hydrogen exchange data can help decipher challenging questions regarding protein structure and dynamics. |
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