Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data

and Computer Simulations

Poster Abstracts

100

65-POS

Board 25

Modeling the Partition of Carvedilol in Lipid Bilayers Using All-Atom Molecular

Dynamics Simulations

Williams E. Miranda

, Van A. Ngo, Sergei Y. Noskov.

University of Calgary, Calgary, AB, Canada.

Heart disease is the primary global cause of deaths with 17.3 million fatalities each year. Despite

the tremendous efforts for finding solutions for heart arrhythmias, current drugs have dangerous

side-effects, increasing rather than decreasing the fatal probabilities. Carvedilol is a β-blocker

that has shown to have encouraging antiarrhythmic effects. Recent experimental evidence

suggest that carvedilol modulates the activity of the cardiac ryanodine receptor (RyR2), a

membrane protein responsible for calcium homeostasis in cardiac cells. This suggests that the

drug must traverse the cytoplasmic membrane to reach RyR2 which is located in the

sarcoplasmic reticulum. Although there are experimental studies on carvedilol partitioning in

model membranes, no atomistic insight into this process is currently available. In this work, we

aim to study the partition of carvedilol into lipid bilayers using all-atom molecular dynamics

simulation (MD). We performed a systematic quantum-based parameterization for carvedilol.

Then, we used umbrella sampling, replica exchange and steered MD simulations to thoroughly

sample conformational ensembles of carvedilol during the partition process, and to obtain

converged free energy profiles. Our preliminary results from umbrella sampling simulations

show small energetic barriers for the partitioning process of the drug in its neutral state. We seek

to explore the energetic relations between rotations of carvedilol with respect to the distance

from the lipid bilayer. We also aim to simulate the partition for charged carvedilol for

comparison with the neutral one. These atomistic simulations will provide insights at the

molecular level on how carvedilol interacts with the lipid membrane, as a first step to understand

its action mechanism on RyR2.