Hydrolysis of aspartic acid phosphoramidate nucleotides: a comparative quantum chemical study.
L-Aspartic acid has recently been found to be a good leaving group during HIV reverse transcriptase catalyzed incorporation of deoxyadenosine monophosphate (dAMP) in DNA. This showed that L-Asp is a good mimic for the pyrophosphate moiety of deoxyadenosine triphosphate. The present work explores the thermochemistry and mechanism for hydrolysis of several models for L-aspartic-dAMP using B3LYP/DGDZVP, MP2/6-311++G** and G3MP2 level of theory. The effect of the new compound is gradually investigated: starting from a simple methyl amine leaving group up to the aspartic acid leaving group. The enzymatic environment was mimicked by involving two Mg(2+) ions and some important active site residues in the reaction. All reactions are compared to the corresponding O-coupled leaving group, which is methanol for methyl amine and malic acid for aspartic acid. With methyl amine as a leaving group a tautomeric associative or tautomeric dissociative mechanism is preferred and the barrier is lower than the comparable mechanism with methanol as a leaving group. The calculations on the aspartic acid in the enzymatic environment show that qualitatively the mechanism is the same as for triphosphate but the barrier for hydrolysis by the associative mechanism is higher for L-aspartic-dAMP than for L-malic-dAMP and pyrophosphate.
Michielssens
Servaas
S
Katholieke Universiteit Leuven, Department of Chemistry and LMCC-Mathematical Modeling and Computational Science Center, Leuven, Belgium. servaas.michielssens@chem.kuleuven.be
Tien Trung
Nguyen
N
Froeyen
Matheus
M
Herdewijn
Piet
P
Tho Nguyen
Minh
M
Ceulemans
Arnout
A
D000577:Amides / Q000737:chemistry*; D001224:Aspartic Acid / Q000737:chemistry*; D020134:Catalytic Domain; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D006868:Hydrolysis; D008274:Magnesium / Q000737:chemistry; D008293:Malates / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D010756:Phosphoric Acids / Q000737:chemistry*; D011789:Quantum Theory
D000577:Amides; D008293:Malates; D009711:Nucleotides; D010756:Phosphoric Acids; D001224:Aspartic Acid; C030298:malic acid; C011067:phosphoramidic acid; D054303:HIV Reverse Transcriptase; D008274:Magnesium