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Computational investigation of kinetics of cross‐linking reactions in proteins: Importance in structure prediction
Author(s) -
Bandyopadhyay Pradipta,
Kuntz Irwin D.
Publication year - 2009
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.21083
Subject(s) - chemistry , kinetics , cytochrome c , molecular dynamics , ionic strength , biological system , computational chemistry , biochemistry , physics , quantum mechanics , aqueous solution , mitochondrion , biology
Abstract The determination of protein structure using distance constraints is a new and promising field of study. One implementation involves attaching residues of a protein using a cross‐linking agent, followed by protease digestion, analysis of the resulting peptides by mass spectroscopy, and finally sequence threading to detect the protein folds. In the present work, we carry out computational modeling of the kinetics of cross‐linking reactions in proteins using the master equation approach. The rate constants of the cross‐linking reactions are estimated using the pKas and the solvent‐accessible surface areas of the residues involved. This model is tested with fibroblast growth factor (FGF) and cytochrome C. It is consistent with the initial experimental rate data for individual lysine residues for cytochrome C. Our model captures all observed cross‐links for FGF and almost 90% of the observed cross‐links for cytochrome C, although it also predicts cross‐links that were not observed experimentally (false positives). However, the analysis of the false positive results is complicated by the fact that experimental detection of cross‐links can be difficult and may depend on specific experimental conditions such as pH, ionic strength. Receiver operator characteristic plots showed that our model does a good job in predicting the observed cross‐links. Molecular dynamics simulations showed that for cytochrome C, in general, the two lysines come closer for the observed cross‐links as compared to the false positive ones. For FGF, no such clear pattern exists. The kinetic model and MD simulation can be used to study proposed cross‐linking protocols. © 2008 Wiley Periodicals, Inc. Biopolymers 91: 68–77, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com