Metabolite fibrils are responsible for wide variety of inherited pediatric metabolite disorders. [1] We elucidate inhibition mechanisms of adenine, phenylalanine, and tyrosine fibrils with polyphenol inhibitors of epigallocatechin gallate (EGCG) and tannic acid (TA). We preformed simulations with each metabolite in the solvated form and crystalline forms interacting with each of the three inhibitors. [2] We calculated average inhibitor-metabolite binding enthalpies to estimate binding capabilities of each inhibitor. We found that EGCG and TA have the same binding energy per metabolite in each when comparing within solvated or crystalline phases. TA has the ability to bind to more metabolites than EGCG in solvated phase, thus is more effective inhibiting fibril formation at early stages. TA and EGCG have equal binding energies per metabolite and can binding at similar propensities to crystalline metabolites, therefore they are equally effective at later stages of fibril formation. Next we determined the disease mechanism of the metabolites tyrosine, adenine, and tryptophan, due to the fact that fibrils are destructive with interference of cellular membrane rather than cellular function[3]. We used PC lipid based membrane, due to its composition in mammalian cellular membranes and combination PC/PS membrane because PS molecules are involved in signaling for cellular apoptosis. For each metabolite crystal with a membrane we took different orientations to determine which binds most favorably to the membrane. We compared our results with colorimetric experiments provided by collaborators. We determined that tyrosine binds most favorable when zwitterion layer is parallel to that of membrane; adenine crystal binds most favorably when plane of molecule is parallel to that of membrane; and tryptophan binds most favorably when zwitterion layer is in direct contact with membrane.

Molecular dynamics simulations of inhibition and disease mechanisms of metabolite fibrils

255th National Meeting (2018)

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