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.