Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

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.

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