bi6b00873_si_002.xlsx (11.46 kB)
Aspects of Weak Interactions between Folate and Glycine Betaine
dataset
posted on 2016-10-21, 00:00 authored by Purva
P. Bhojane, Michael R. Duff, Khushboo Bafna, Gabriella P. Rimmer, Pratul K. Agarwal, Elizabeth E. HowellFolate, 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
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