Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 505, Issue 1, Pages 33-41Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2010.10.010
Keywords
FEP; BIE; QM/MM; Isoforms; LDH
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Funding
- Ministry of Science and Higher Education, Poland [NN204/1579/33]
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We present QM/MM calculations that show differences in geometries of active sites of M-4 and H-4 isoforms of human LDH ligated with oxamate, pyruvate or L-lactate. As the consequence of these differences, binding isotope effects of the methyl hydrogen atoms of pyruvate and L-lactate may be used to experimentally distinguish these isoforms. Based on the FEP calculations we argue that L-lactate is a better candidate for the experimental studies. Our calculations of energies of interactions of ligands with the active site residues provide explanation for the observed experimentally sensitivity to inhibition of the M-4 isoenzyme isoform and pinpoint the differences to interactions of the ligand with the histidine residue. We conclude that pyruvate interacts much stronger in the active site of H-4 than M-4 isoform and that the latter interactions are weaker than with water molecules in the aqueous solution. (C) 2010 Elsevier Inc. All rights reserved.
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