Modeling Hydroxide in Classical Proton Hopping Simulations and Amyloid beta Membrane Pores

Author

Ankita Dutta, The Graduate Center, City University of New York

Date of Degree

6-2024

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biochemistry

Advisor

Themis Lazarids

Committee Members

Mark E. Tuckerman

Marilyn Gunner

Sharon Loverde

Tom Kurtzman

Subject Categories

Biochemistry | Biophysics | Computational Chemistry

Keywords

Classical Molecular Dynamics, Hydroxide ion, Monte Carlo, Proton Hopping

Abstract

H3O+ and OH- ions display anomalously large diffusion coefficients, a property that is often attributed to their ability to perform structural diffusion which allow these ions to move through aqueous solutions by sequential proton transfers, also known as ‘Grotthuss hopping’. A rearrangement of the local solvation structure is known to be the prerequisite for proton transfer events via these ions. Studying this phenomenon using classical molecular dynamics simulations that do not allow bond rearrangements poses significant obstacles. Here we use a Monte Carlo augmented classical Molecular Dynamics method called the MOBHY algorithm which allows instantaneous changes in protonation states in aqueous and biomolecular systems. The implementation of OH- mediated proton hopping into this algorithm is particularly challenging as classical force fields are known to stabilize hypercoordinated solvation structures of the OH- ion in bulk water system. Here a classical OH- model with the charge of oxygen distributed amongst 3 auxiliary particles is proposed which favors lower coordination number by accepting 3 hydrogen bonds and donating 1. The model was implemented in MOBHY and experimental and theoretical mobilities were qualitatively reproduced in bulk water systems and under nanoconfinement. The model was then used to study the passive permeation of H3O+ and OH- ions through pure DMPC bilayers. Our preliminary observations indicate that the process of passive permeation of H3O+ is dominated by the Grotthuss hopping mechanism, while the vehicular diffusion mechanism dominates the process of passive permeation of the OH- ion through pure lipid bilayers. Many degenerative diseases are characterized by aberrant protein aggregation that also lead to perturbation or permeabilization of lipid membranes. Here, the possible pore-forming structures of oligomers of Aβ25-35 peptide were investigated in a POPC/POPG membrane. Aβ25-35 is the shortest fragment of the amyloid β peptide that retains important physical and biological activities of the full-length peptide. Octameric and decameric β-barrels produced by this peptide of different topologies were considered and the best models were subjected to multi microsecond all-atom molecular dynamics simulations. Two decameric structures were kinetically stable in membranes on this time scale: an imperfectly closed antiparallel β-barrel with K28 in the pore lumen and a short parallel β-barrel with K28 toward the membrane interface. Both structures exhibit dehydrated gaps in the pore lumen, which were larger for the antiparallel barrel. Based on these results, the experimental cation selectivity, the dependence of ion channel activity on voltage direction, and certain mutation data, the parallel model was found to be more compatible with experimental data.

Recommended Citation

Dutta, Ankita, "Modeling Hydroxide in Classical Proton Hopping Simulations and Amyloid beta Membrane Pores" (2024). CUNY Academic Works.
https://academicworks.cuny.edu/gc_etds/6082