pH Dependence of Stability of the 10th Human Fibronectin Type III Domain: A Computational Study.

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pH Dependence of Stability of the 10th Human Fibronectin Type III Domain: A Computational Study. Abstract Text:

Buddhadeb Mallik,Li Zhang,Shohei Koide,Dimitrios Morikis,

We present detailed computational studies based on electrostatic calculations to evaluate the origins of pKa values and the pH dependence of stability for the 10th type III domain of human fibronectin (FNfn10). One of our goals is to validate the calculation protocols by comparison to experimental data (Koide, A.; Jordan, M. R.; Horner, S.; Batori, V.; Koide, S. Biochemistry 2001, 40, 10326-10333). Another goal is to evaluate the sensitivity of the calculated ionization free energies and apparent pKa values on local structural fluctuations, which do not alter the structural convergence to a particular architecture, by using a complete ensemble of solution NMR structures and the NMR average minimized structure of FNfn10 (Main, A. L.; Harvey, T. S.; Baron, M.; Boyd, J.; Campbell, I. D. Cell 1992, 71, 671-678). Our calculations demonstrate that, at high ionic strength, FNfn10 is more stable at low pH compared to neutral pH, in overall agreement with experimental data. This behavior is attributed to contributions from unfavorable Coulombic interactions in a surface patch for the pairs Asp7-Glu9 and Asp7-Asp23. The unfavorable interactions are decreased at low pH, where the acidic residues become neutral, and are further decreased at high ionic strength because of increased screening by salt ions. Elimination of the unfavorable interactions in the theoretical mutants Asp7Asn (D7N) and Asp7Lys (D7K) produce higher calculated stabilities at neutral pH and any ionic strength compared to the wild-type, in agreement with the experimental data. We also discuss subtleties in the calculated apparent pKa values and ionization free energies, which are not in agreement with the experimental data. This work demonstrates that comparative electrostatic calculations can provide rapid predictions of pH-dependent properties of proteins and can be significant aids in guiding the design of proteins with tailored properties.

pH Dependence of Stability of the 10th Human Fibronectin Type III Domain: A Computational Study. Publishing Authors By Initials

B Mallik,L Zhang,S Koide,D Morikis,

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MEDLINE DATE: 2008 Jan-Feb

pH Dependence of Stability of the 10th Human Fibronectin Type III Domain: A Computational Study. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Biotechnology progress

VOLUME: 24

Page Numbers: 48-55

Journal Abbreviation: Biotechnol. Prog.

ISSN: 8756-7938

DAY: 13

MONTH: 10

YEAR: 2007

pH Dependence of Stability of the 10th Human Fibronectin Type III Domain: A Computational Study. Information

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LANGUAGE: eng

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AFFILIATION: Departments of Bioengineering and Chemistry, University of California at Riverside, Riverside, California 92521, and Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, Illinois 60637.

Country: United States

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MEDLINETA: Biotechnol Prog

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