Aspects of Weak Interactions between Folate and Glycine Betaine
datasetposted on 21.10.2016, 00:00 by Purva P. Bhojane, Michael R. Duff, Khushboo Bafna, Gabriella P. Rimmer, Pratul K. Agarwal, Elizabeth E. Howell
Folate, or vitamin B9, is an important compound in one-carbon metabolism. Previous studies have found weaker binding of dihydrofolate to dihydrofolate reductase in the presence of osmolytes. In other words, osmolytes are more difficult to remove from the dihydrofolate solvation shell than water; this shifts the equilibrium toward the free ligand and protein species. This study uses vapor-pressure osmometry to explore the interaction of folate with the model osmolyte, glycine betaine. This method yields a preferential interaction potential (μ23/RT value). This value is concentration-dependent as folate dimerizes. The μ23/RT value also tracks the deprotonation of folate’s N3–O4 keto–enol group, yielding a pKa of 8.1. To determine which folate atoms interact most strongly with betaine, the interaction of heterocyclic aromatic compounds (as well as other small molecules) with betaine was monitored. Using an accessible surface area approach coupled with osmometry measurements, deconvolution of the μ23/RT values into α values for atom types was achieved. This allows prediction of μ23/RT values for larger molecules such as folate. Molecular dynamics simulations of folate show a variety of structures from extended to L-shaped. These conformers possess μ23/RT values from −0.18 to 0.09 m–1, where a negative value indicates a preference for solvation by betaine and a positive value indicates a preference for water. This range of values is consistent with values observed in osmometry and solubility experiments. As the average predicted folate μ23/RT value is near zero, this indicates folate interacts almost equally well with betaine and water. Specifically, the glutamate tail prefers to interact with water, while the aromatic rings prefer betaine. In general, the more protonated species in our small molecule survey interact better with betaine as they provide a source of hydrogens (betaine is not a hydrogen bond donor). Upon deprotonation of the small molecule, the preference swings toward water interaction because of its hydrogen bond donating capacities.
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p Kpreference swingsRTPrevious studiesfolate dimerizesfolate showsurface area approachMolecular dynamics simulationsatom typesprotein speciesmethod yieldsprotonated speciesGlycine Betaine Folateglycine betainefolate atomsglutamate tailmodel osmolytehydrogen bond donordihydrofolate reductaseosmometry measurementsmolecule surveywater interactionα valuesone-carbon metabolismvitamin B 9hydrogen bondWeak Interactionsvapor-pressure osmometrydihydrofolate solvation shellsolubility experiments