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Modeling Flexible Molecules in Solution: A pKa Case Study

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dc.contributor.authorHaworth, Naomi
dc.contributor.authorWang, Qinrui
dc.contributor.authorCoote, Michelle
dc.date.accessioned2019-06-11T06:48:40Z
dc.date.issued2017
dc.date.updated2019-03-24T07:17:25Z
dc.description.abstractContinuum solvation models have been incredibly successful for the computationally efficient study of chemical reactions in solution. However, their development and application has generally been on focused on investigations of small, rigid molecules. Additional factors must be considered when studying large, flexible and multiply ionizable species. These include whether the use of thermocycle or entirely solution-phase approaches are more appropriate for the calculation of solution-phase free energies, which metrics can be used to reliably identify the conformation(s) adopted by flexible molecules in solution, and how errors due to inaccuracies in the prediction of low energy vibrational frequencies can be avoided. Here we explore these issues using the calculation of pKas for a diverse set of amine-containing species as a case study. We show that thermocycle-based approaches should only be applied where there are relatively small structural changes between the gas- and solution-phase molecular geometries, and that these methods are generally not appropriate for conformational searching. Using gas- or solution-phase energies or gas-phase free energies can also lead to errors in the identification of the most stable molecular conformation(s). Scaling of low energy vibrational modes (i.e., use of the quasi-harmonic oscillator approximation) is helpful, however care must be taken to ensure modes that change as part of the reaction are not disregarded. Entirely solution-phase approaches to the Gibbs free energy and hence pKa calculations were found to yield accurate pKa values for the amine test set studied when each charged site is complexed with an explicit water molecule and a proton exchange scheme is applied with an appropriately chosen reference acid.en_AU
dc.description.sponsorshipThis work was funded via the Australian Research Council Centre of Excellence for Electromaterials Science (CE140100012).en_AU
dc.format.mimetypeapplication/pdfen_AU
dc.identifier.issn1089-5639en_AU
dc.identifier.urihttp://hdl.handle.net/1885/164015
dc.language.isoen_AUen_AU
dc.publisherAmerican Chemical Societyen_AU
dc.relationhttp://purl.org/au-research/grants/arc/CE140100012en_AU
dc.rights© 2017 American Chemical Societyen_AU
dc.sourceJournal of Physical Chemistry Aen_AU
dc.titleModeling Flexible Molecules in Solution: A pKa Case Studyen_AU
dc.typeJournal articleen_AU
local.bibliographicCitation.issue27en_AU
local.bibliographicCitation.lastpage5225en_AU
local.bibliographicCitation.startpage5217en_AU
local.contributor.affiliationHaworth, Naomi, College of Science, ANUen_AU
local.contributor.affiliationWang, Qinrui, College of Science, ANUen_AU
local.contributor.affiliationCoote, Michelle, College of Science, ANUen_AU
local.contributor.authoremailu4031074@anu.edu.auen_AU
local.contributor.authoruidHaworth, Naomi, u5659913en_AU
local.contributor.authoruidWang, Qinrui, t1814en_AU
local.contributor.authoruidCoote, Michelle, u4031074en_AU
local.description.embargo2037-12-31
local.description.notesImported from ARIESen_AU
local.identifier.absfor030701 - Quantum Chemistryen_AU
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciencesen_AU
local.identifier.ariespublicationa383154xPUB7488en_AU
local.identifier.citationvolume121en_AU
local.identifier.doi10.1021/acs.jpca.7b04133en_AU
local.identifier.scopusID2-s2.0-85024864336
local.identifier.thomsonID000405761800017
local.identifier.uidSubmittedBya383154en_AU
local.publisher.urlhttps://pubs.acs.org/en_AU
local.type.statusPublished Versionen_AU

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