Download ABSTRACT Cofactors are essential small molecules that

ABSTRACT
Cofactors are essential small molecules that help catalyse a variety of enzymatic
reactions. They are either inorganic (e.g., metal ions such as Mg2+, Mn2+, and Zn2+) or organic
(e.g., NAD and ATP). Herein we have performed systematic studies on cofactor
conformations from simple metal ions to complex nucleotides to elucidate their various
conformations and how a given cofactor can bind to a protein for specific function. First, we
have examined the geometry of metal ions in the Cambridge Structural Database to determine
the key factors governing metal-ligand distances and “conformations” of metal complexes.
Second, we have analysed the conformational variability of organic cofactors (NAD(P), ADP,
GDP, ATP, and GTP). A key difference in the multi-atom organic cofactors from single metal
ion is (a) its large conformational space due to its multiple rotatable bonds and (b) its diverse
chemical groups, which are open to a variety of interactions during catalysis. These cofactors
mostly prefer extended conformations upon binding to proteins to maximize interactions with
the binding site residues. Some distinct nucleotide conformations were correlated to specific
enzyme binding domain and function through CATH code and EC number. Torsion angles
were computed to distinguish enzyme-bound nucleotide conformations or functions, especially
in NAD(P). Knowledge of enzyme-bound cofactor conformations would certainly be of
relevance to rational drug design since all these cofactors are involved in crucial
metabolic/signalling pathways.
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