Methyltetrahydrofolate:corrinoid/iron-sulfur Protein Methyltransferase (MeTr): Protonation State of the Ligand and Active-Site Residues

dc.contributor.authorAlonso, Hernan
dc.contributor.authorCummins, Peter
dc.contributor.authorGready, Jill
dc.date.accessioned2015-12-10T21:53:43Z
dc.date.issued2009
dc.date.updated2016-02-24T10:26:57Z
dc.description.abstractMethyltetrahydrofolate:corrinoid/iron-sulfur protein methyltransferase (MeTr) catalyzes the transfer of the N5-methyl group from N5- methyltetrahydrofolate (CH3THF) to the cobalt center of a corrinoid/iron-sulfur protein, a reaction similar to that of cobalamin-dependent methionine synthase (MetH). For such a reaction to occur, CH3THF is expected to be activated by a stereospecific protonation at the N5 position. It has been shown experimentally that binding to MeTr is associated with a pK a increase and proton uptake. The enzyme could achieve this by binding the unprotonated form of CH3THF, followed by specific protonation at the correct orientation. Here we have used computational approaches to investigate the protonation state of the ligand and active-site residues in MeTr. First, quantum mechanical (QM) methods with the PCM solvation model were used to predict protonation positions and pKa values of pterin, folate, and their analogues in an aqueous environment. After a reliable calibration of computational and experimental results was obtained, the effect of the protein environment was then considered. Different protonation states of CH3THF and activesite aspartic residues (D75 and D160) were investigated using QM calculations of active-site fragment complexes and the perturbed quantum atom (PQA) approach within QM/MM simulations. The final free energy results indicate that the N5 position of the tetrahydropterin ring is the preferred protonation position of CH3THF when bound to the active site of MeTr, followed by Asp160. We also found that the active-site environment is likely to increase the pKa of N5 by about 3 units, leading to proton uptake upon CH3THF binding, as observed experimentally for MeTr. Some implications of the results are discussed for the MetH mechanism.
dc.identifier.issn1520-6106
dc.identifier.urihttp://hdl.handle.net/1885/38619
dc.publisherAmerican Chemical Society
dc.sourceJournal of Physical Chemistry B
dc.subjectKeywords: Active site; Aqueous environment; Computational approach; Methionine synthase; Methyl group; Methyltransferases; Proton uptake; Protonation state; Quantum atoms; Quantum mechanical method; Site environments; Solvation models; Stereospecific; Binding energ
dc.titleMethyltetrahydrofolate:corrinoid/iron-sulfur Protein Methyltransferase (MeTr): Protonation State of the Ligand and Active-Site Residues
dc.typeJournal article
local.bibliographicCitation.issue44
local.bibliographicCitation.lastpage96
local.bibliographicCitation.startpage14787
local.contributor.affiliationAlonso, Hernan, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationCummins, Peter, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationGready, Jill, College of Medicine, Biology and Environment, ANU
local.contributor.authoremailu9508363@anu.edu.au
local.contributor.authoruidAlonso, Hernan, u3999873
local.contributor.authoruidCummins, Peter, u9508363
local.contributor.authoruidGready, Jill, u9508375
local.description.embargo2037-12-31
local.description.notesImported from ARIES
local.identifier.absfor030799 - Theoretical and Computational Chemistry not elsewhere classified
local.identifier.absfor030701 - Quantum Chemistry
local.identifier.absfor060107 - Enzymes
local.identifier.ariespublicationu4020362xPUB164
local.identifier.citationvolume133
local.identifier.doi10.1021/jp900181g
local.identifier.scopusID2-s2.0-72449124231
local.identifier.thomsonID000271105600031
local.identifier.uidSubmittedByu4020362
local.type.statusPublished Version

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