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Effects of protonation on the hydrolysis of triphosphate in vacuum and the implications for catalysis by nucleotide hydrolyzing enzymes

Kiani, Farooq Ahmad ; Fischer, Stefan

In: BMC Biochemistry, 17 (2016), Nr. 12. pp. 1-13. ISSN 1471-2091

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Abstract

Background: Nucleoside triphosphate (NTP) hydrolysis is a key reaction in biology. It involves breaking two very stable bonds (one P–O bond and one O–H bond of water), in either a concurrent or a sequential way. Here, we systematically examine how protonation of the triphosphate affects the mechanism of hydrolysis. Results: The hydrolysis reaction of methyl triphosphate in vacuum is computed with protons in various numbers and position on the three phosphate groups. Protonation is seen to have a strong catalytic effect, with the reaction mechanism depending highly on the protonation pattern. Conclusion: This dependence is apparently complicated, but is shown to obey a well-defined set of rules: Protonation of the α- and β-phosphate groups favors a sequential hydrolysis mechanism, whereas γ-protonation favors a concurrent mechanism, the two effects competing with each other in cases of simultaneous protonation. The rate-limiting step is always the breakup of the water molecule while it attacks the γ-phosphorus, and its barrier is lowered by γ-protonation. This step has significantly lower barriers in the sequential reactions, because the dissociated γ-metaphosphate intermediate (PγO3 −) is a much better target for water attack than the un-dissociated γ-phosphate (−PγO4 2−). The simple chemical logic behind these rules helps to better understand the catalytic strategy used by NTPase enzymes, as illustrated here for the catalytic pocket of myosin. A set of rules was determined that describes how protonating the phosphate groups affects the hydrolysis mechanism of methyl triphosphate: Protonation of the α- and/or β- phosphate groups promotes a sequential mechanism in which P-O bond breaking precedes the breakup of the attacking water, whereas protonation of the γ-phosphate promotes a concurrent mechanism and lowers the rate-limiting barrier of water breakup. The role played by individual protein residues in the catalytic pocket of triphosphate hydrolysing enzymes can be assigned accordingly.

Item Type: Article
Journal or Publication Title: BMC Biochemistry
Volume: 17
Number: 12
Publisher: BioMed Central; Springer
Place of Publication: London; Berlin; Heidelberg
Date Deposited: 15 Dec 2016 13:44
Date: 2016
ISSN: 1471-2091
Page Range: pp. 1-13
Faculties / Institutes: Service facilities > Interdisciplinary Center for Scientific Computing
Subjects: 540 Chemistry and allied sciences
570 Life sciences
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