In silico study of levodopa in hydrated lipid bilayers at the atomistic level

Abstract

This article presents atomistic molecular dynamics and umbrella sampling simulations of levodopa at various concentrations in hydrated cholesterol-free 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and cholesterol-containing 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayers. Levodopa is the standard medication for Parkinson's disease and is marketed under various trade names; in the context of this article, the levodopa molecule is mostly studied in its zwitterionic form but some results concerning the neutral levodopa are presented as well for comparison purposes. The motivation is to study in detail how levodopa behaves in different hydrated lipid membranes, primarily from the thermodynamic point of view, and reveal aspects of mechanism of its permeation through them. Dependencies of properties on the levodopa concentration are also investigated. Special attention is paid to the calculation of mass density profiles, order parameters and self-diffusion coefficients. Levodopa zwitterions, which form a hydrogen bond network with water and phospholipid molecules, are found to be preferentially located at the water/lipid interface, as well as in the aqueous phase surrounding the cholesterol-free and cholesterol-containing bilayers. This is concluded from the potentials of mean force calculated by umbrella sampling simulations as levodopa is transferred from the lipid to the aqueous phase along an axis perpendicular to the two leaflets of the membranes. © 2021 Elsevier Inc.