Atomistic Model for Simulations of the Sedative Hypnotic Drug 2,2,2-Trichloroethanol

Abstract

2,2,2-Trichloroethanol (TCE) is the active form of the sedative hypnotic drug chloral hydrate, one of the oldest sleep medications in the market. Understanding of TCE’s action mechanisms to its many targets, particularly within the ion channel family, could benefit from the state-of-the-art computational molecular studies. In this direction, we employed de novo modeling aided by the force field toolkit to develop CHARMM36-compatible TCE parameters. The classical potential energy function was calibrated targeting molecular conformations, local interactions with water molecules, and liquid bulk properties. Reference data comes from both tabulated thermodynamic properties and ab initio calculations at the MP2 level. TCE solvation free energy calculations in water and oil reproduce a lipophilic, yet nonhydrophobic, behavior. Indeed, the potential mean force profile for TCE partition through the phospholipid bilayer reveals the sedative’s preference for the interfacial region. The calculated partition coefficient also matches experimental measures. Further validation of the proposed parameters is supported by the model’s ability to recapitulate quenching experiments demonstrating TCE binding to bovine serum albumin.

Cholesterol-like Condensing Effect of Perfluoroalkyl Substances on a Phospholipid Bilayer

“…The corresponding rtf and prm files for PFOA and PFOS generated by MATCH are listed in the Supporting Information. These listed parameters for F atom, including the charge and potential well depth of the van der Waals interactions, are similar to those reported in the literature. , Due to its compatibility with CHARMM FF and ability to generate FF parameters for various molecules, the MATCH server has been widely used for small organic molecules. − …”

Interactions between Rhodamine Dyes and Model Membrane Systems—Insights from Molecular Dynamics Simulations

“…The simple use of the thermodynamic relationship ∆G = −RTlnK P ⇔ K P = exp(−∆G/RT) (R and T being the gas constant and absolute temperature, respectively) is probably not valid, because of different underlying reference states in the experimental and calculated K P , as well as arbitrariness in establishing the water/lipid interphase in the simulations. Still, in a number of computational works, K P is taken as proportional to the integral of the exponential term along the reaction coordinate, thus accounting for both the depth and width of the free energy well [38][39][40][41][42]:…”

Concentration-dependent thermodynamic analysis of the partition process of small ligands into proteins

“…Abiding by the same requirements, independent flooding-MD calculations for the sedative hypnotic drug trichloroethanol [26] and the aqueous-soluble bovine serum albumin [27] further support that the thermodynamic model may be applicable to other two-component interacting systems guided by non-bonded low-affinity interactions ( Table-S4 , Fig. S9 and S10 ).…”