期刊
PROTEIN SCIENCE
卷 14, 期 2, 页码 543-557出版社
WILEY
DOI: 10.1110/ps.0411001705
关键词
protein dynamics; protein energy landscape; protein equilibrium states; amide hydrogen exchange; mass spectrometry
资金
- NIGMS NIH HHS [R01 GM061666, R01 GM61666, T32 GM008515] Funding Source: Medline
Protein amide hydrogen exchange (HDX) is a convoluted process, whose kinetics is determined by both dynamics of the protein and the intrinsic exchange rate of labile hydrogen atoms fully exposed to solvent. Both processes are influenced by a Variety of intrinsic and extrinsic factors. A mathematical formalism initially developed to rationalize exchange kinetics of individual amide hydrogen atoms is now often used to interpret global exchange kinetics (e.g.. as measured in HDX IMS experiments). One particularly, important advantage of HDX MS is direct visualization of Various protein states by observing distinct protein ion Populations with different levels of isotope labeling under conditions favoring correlated exchange (the so-called EXl exchange mechanism). However, mildly denaturing conditions often lead to a Situation where the overall HDX kinetics cannot be clearly classified as either EX1 or EX2. The goal of this work is to develop a framework for a generalized exchange model that takes into account multiple processes leading to amide hydrogen exchange. and does not require that the exchange proceed strictly via EX1 or EX2 kinetics. To achieve this goal, we use a probabilistic approach that assigns a transition probability and a residual protection to each equilibrium state of the protein. When applied to a small protein chymotrypsin inhibitor 2. the algorithm allows complex HDX patterns observed experimentally to be modeled with remarkably good fidelity. On the basis of the model we are now in a position to begin to extract quantitative dynamic information from convoluted exchange kinetics.
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