The coupling of structural fluctuations to hydride transfer in dihydrofolate reductase

Proteins
Ian F Thorpe, Charles L Brooks

Abstract

The energy barrier for hydride transfer in wild-type G121V and G121S variants of Escherichia coli dihydrofolate reductase (DHFR) fluctuates in a time-dependent manner. This fluctuation may be attributed to structural changes in the protein that modulate the site of chemistry. Despite being far from the active site, mutations at position 121 of DHFR reduce the hydride transfer rate of the enzyme. This occurrence has been suggested to arise from modifications to the conformational ensemble of the protein. We elucidate the effects of the G121S and G121V mutations on the hydride transfer barrier by identifying structural changes in the protein that correlate with lowered barriers. The effect of these structural parameters on the hydride transfer barrier may be rationalized by simple considerations of the geometric constraints of the hydride transfer reaction. Fluctuations of these properties are associated with specific backbone dihedral angles of residues within the Methione-20 (M20) loop. The dihedral angle preferences are mediated by interactions with the region of the enzyme in the vicinity of residue 121 and are translated into distinct ligand conformations. We predict mutations within the M20 loop that may alter the conformat...Continue Reading

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Citations

Jul 20, 2010·Interdisciplinary Sciences, Computational Life Sciences·Kara E Ranaghan, Adrian J Mulholland
Feb 1, 2006·Biochemistry·Lin WangAmnon Kohen
Mar 28, 2009·Journal of the American Chemical Society·Karunesh Arora, Charles L Brooks Iii
Feb 25, 2009·The Journal of Physical Chemistry. B·Malika KumarasiriSharon Hammes-Schiffer
Jul 29, 2006·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Rudolf K AllemannRichard S Swanwick
Jul 29, 2006·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Sharon Hammes-Schiffer, James B Watney
Jul 29, 2006·Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences·Lin WangAmnon Kohen
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Jan 18, 2006·Microbial Cell Factories·Pratul K Agarwal
Apr 7, 2005·Proceedings of the National Academy of Sciences of the United States of America·Kim F WongSharon Hammes-Schiffer
Nov 30, 2006·Proceedings of the National Academy of Sciences of the United States of America·Brad BennettChris Dealwis
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Aug 10, 2006·Chemical Reviews·David D BoehrPeter E Wright
Sep 15, 2005·Journal of the American Chemical Society·Ian F Thorpe, Charles L Brooks
Oct 27, 2005·Journal of the American Chemical Society·Pratul K Agarwal

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