Alpha-hemolysin (α-HL) is a non-ligand-gated ion channel used to measure the size and charge of macromolecules such as DNA across a membrane through an analysis of ionic current reduction. In most experimental measurements of ion current, membranes with 1,2-diphytanoyl-sn-glycero-3-phosphocholine (PHPC) are used; however, most molecular dynamics (MD) simulations use membranes composed of a more common lipid: 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). Additionally, other studies have not assessed the importance of equilibration time for the lipid membrane/protein system nor have they adequately explained why attempting to truncate the protein leads to dysfunction of the protein gate and subsequent ionic current values which differ significantly from experiment. In this study, we quantify the importance of equilibration time, structural truncation of α-HL, and selection of lipids for membrane bilayers.<br/><br/>The 5-hydroxytryptamine receptor (5-HT3) is the principle receptor responsible for modulating a wide range of neurological and digestive functions. The second part of this work is to use MD simulations to quantify the differences in 5-HT3 structure and function with respect to previous studies that utilized shorter equilibration times and simple membranes composed of POPC lipids. Instead, we have used a more representative lipid composition with respect to that found in neural membranes: 7:7:6 POPC/1-stearoyl-2-docosahexaenoyl-sn-glyerco-3-phosphocholine (SDPC)/cholesterol. Moreover, we compare the apo form of 5-HT3 compared to 5-HT3 with five 5-HT (serotonin) molecules docked into a native/equilibrated (as opposed to crystal) form of 5-HT3 over several microseconds. This work supports the experimental design of a field effect transistor (FET) we are developing to measure the presence of ligands such as neurotransmitters, neuropeptides, and drug molecules in solution.

Importance of equilibration time, structure truncation, and membrane lipid type for simulations of ion channels

254th National Meeting (2017)

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