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Abstract

Comparison and multiple alignments of amino acid sequences of a representative number of related enzymes demonstrate the existence of certain positions of amino acid residues which are permanently reproducible in all members of the whole family. The use of the bioinformatic approach revealed conservative residues in each of the related enzymes and ranked amino acid conservatism for the overall enzymatic catalysis. Glycine and aspartic acid residues were shown to be the most essential for structure and catalytic activity of enzymes. Amino acid residues forming catalytic subsite of the active site of enzymes are always highly conservative. Analysis revealed that aspartic acid carboxyl group is the most frequently employed nucleophilic (in deprotonated form) and electrophilic (in protonated form) agent involved in activation of molecules by the mechanism of general base and acidic catalyses in the catalytic sites of enzymes. Glycine is a unique amino acid possessing the highest possibilities for rotation along C-C and C-N bonds of the polypeptide chain. The conservative fixation of the glycine residue in polypeptide chains of related enzymes provides a possibility for directed assembly of amino acid residues into the catalytic subsite structure. It is possible that the conservative glycines provide known conformational mobility of the protein and the active site. Methods of molecular modeling were used for analysis of structural substitutions of conservative and non-conservative glycines and their effects on geometry of catalytic site of typical hydrolases. The substitution of glycine(s) for alanine significantly altered the catalytic site structures.

In Silico Identification of Significant Detrimental Missense Mutations of EGFR and Their Effect with 4-Anilinoquinazoline-Based Drugs

“…This server is also efficient in sampling the vast conformation space of biomolecules in both length and time scales. Divergence in mutant structure with native structure is due to mutation, deletions, and insertions [26], and the deviation between the two structures could alter the functional activity [27] with respect to binding efficiency of the inhibitors which is evaluated by their RMSD values.…”

Functional and Structural Characterization of Polymorphisms in <I>MSH2</I> Gene Using Computational Tools

“…Divergence in mutant structure with native structure is due to mutation, deletions, and insertions, 52 and the deviation between the two structures is evaluated by their RMSD (root mean square deviation) values which could affect stability and functional activity. 53 Higher the RMSD value more will be the deviation between native and mutant type structures and which in turn changes their functional activity. The native protein structure (2O8C) of MSH2 gene is shown in Figure 2(a).…”

Postgenomic chemistry: New problems and challenges

“…The catalytic site of the chymotrypsin family includes Ser195, His57, and Asp102, whereas the catalytic site of the alkaline phosphatase family includes Asp51, Asp369, His370, Asp327, His412, His331, and Ser102. Catalysis by inorganic phosphatase involves Glu20, Asp65, Asp70, and Asp102 [35].…”

“…The essential role of Gly for structural function of enzyme-active sites was demonstrated by molecular modeling method [35]. Thus, the presence of conservative glycines may explain the structural paradox of enzymatic catalysis, when completely identical active sites are formed from completely distinct protein sequences.…”