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P.N. Farnsworth, P.H. Frederikse, J.E. Kerrigan; Structural Basis of Chaperone Inhibition by Alfa A-Crystallin Mutant F71G . Invest. Ophthalmol. Vis. Sci. 2003;44(13):2370.
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Purpose: The single mutation, F71G, (Sharma et al., 2000) inhibits chaperone activity of αA and its mini-chaperone, K70 to K88. Our goal is to use a molecular dynamics simulation of the wild type αA ß-sheet of D69-H79 and its mutant to investigate the structural basis for this inhibition. Methods: The GROMACS molecular dynamics software package was used to simulate the ß-sheets formed when the wt and mutant sequences are self-aligned in an anti-parallel fashion and to determine the effects of increased temperature on the stability of these ß-sheets. Results: Unlike the linear ß-sheets modeled in vacuo, our simulations of both sequences in a water box produce the most common right-handed twist stabilized by hydrogen bonds, hydrophobic interactions and salt bridges. With increased temperature, which usually accompanies increased chaperone activity; the F71 is essential for unwinding of the ß-sheet resulting in an increased surface area exposure and volume. Increased temperature of the mutant results in a net stabilization of the ß-sheet resulting in a decreased surface area exposure and volume. Conclusion: The D69-H79 sequence of αA has the structural flexibility to modulate subunit-subunit interactions and chaperone activity. Our procedure provides a method for dynamic structural simulations and evaluation of mutations prior to experimentation.
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