Conner Herndon

Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds.

Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous solubility-diffusion model, which requires calculation of the potential of mean force and position-dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the permeability of a model DMPC bilayer to urea, benzoic acid, and codeine. We compare umbrella sampling, replica exchange umbrella sampling, adaptive biasing force, and multiple-walker adaptive biasing force for the calculation of the transmembrane PMF. No definitive advantage for any of these methods in their ability to predict the membrane permeability coefficient Pm was found, provided that a sufficiently long equilibration is performed. For diffusivities, a Bayesian inference method was compared to a generalized Langevin method, both being sensitive to chosen parameters and the slow relaxation of membrane defects. Agreement within 1.5 log units of the computed Pm with experiment is found for all permeants and methods. Remaining discrepancies can likely be attributed to limitations of the force field as well as slowly relaxing collective movements within the lipid environment. Numerical calculations based on model profiles show that Pm can be reliably estimated from only a few data points, leading to recommendations for calculating Pm from simulations.

Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos.

It is widely believed that one major life-threatening transition to chaotic fibrillation occurs via spiral-wave breakup that is preceded by spatiotemporal dispersion of refractoriness due to alternations in the duration of the cardiac action potential (AP). However, recent clinical and experimental evidence suggests that other characteristics of the AP may contribute to, and perhaps drive, this dangerous dynamical instability. To identify the relative roles of AP characteristics, we performed experiments in rabbit hearts under conditions to minimize AP duration dynamics which unmasked pronounced AP amplitude alternans just before the onset of fibrillation. We used a simplified ionic cell model to derive a return map and a stability condition that elucidates a novel underlying mechanism for AP alternans and spiral breakup. We found that inactivation of the sodium current is key to developing amplitude alternans and is directly connected to conduction block and initiation of arrhythmias. Simulations in 2D where AP amplitude alternation led to turbulence confirm our hypothesis.

Accelerating the use of molecular modeling in the high school classroom with VMD Lite

It is often difficult for students to develop an intuition about molecular processes, which occur in a realm far different from day‐to‐day life. For example, thermal fluctuations take on hurricane‐like proportions at the molecular scale. Students need a way to visualize realistic depictions of molecular processes to appreciate them. To this end, we have developed a simplified graphical interface to the widely used molecular visualization and analysis tool Visual Molecular Dynamics (VMD) called VMD lite. We demonstrate the use of VMD lite through a module on diffusion and the hydrophobic effect as they relate to membrane formation. Trajectories from molecular dynamics simulations, which students can interact with freely, illustrate the dynamical behavior of lipid molecules and water. VMD lite was tested by ∼70 students with overall positive reception. Remaining deficiencies in conceptual understanding were noted, however, and the module has been revised in response.

Electrocardiogram reconstruction from high resolution voltage optical mapping

Electrocardiogram recordings during opucal mapping experiments in heart tissue are commonly used tu monitor the health of the preparation and to obtain dominant frequencies during arrhythmic and defibrillatory studies. However the use of ECG reconstructed from optical mapping is seldom used and to date it has not been strictly validated. In this manuscript we present the first detailed validation and comparison of Optical Mapping ECG, or OM-ECG, with standard ECG recordings by calculating the electrostatic potential in space as a function of the voltage measured optically and describe the different approximations that can be used to obtain unipolar or bipolar ECG recordings. We found that in small/medium hearts, such as rabbits, leads that are aligned apex to base only require activation recording from one surface (anterior or posterior) for the OM-ECG to match the ECG while leads aligned left to right may require both an anterior and posterior optical mapping recording. The discrepancy between leads is due to symmetries in the ventricular activations. In the case of ischemic hearts where activations even-out more, the match between the OM-ECG and standard ECG may require only one surface recording for both left-right and base-apex leads. We believe that this methodology has two main and direct applications in the study of cardiac dynamics. The first is during studies of defibrillation where information after the shock may be crucial in the development of new strategies, OM-ECGs do not suffer the current artifacts of standard ECGs during shocks and can be calculated during the entire activation. We present examples in rabbit ventricles where even low amplitude pacing artifacts are captured by the ECG but do not appear in the OM-ECG. The second use of this technique is for reconstructions of intramural dynamics in larger hearts where differences between the ECG and OM-ECG obtained from anterior and posterior recordings can be used to derive the intramural activation.Electrocardiogram recordings during opucal mapping experiments in heart tissue are commonly used tu monitor the health of the preparation and to obtain dominant frequencies during arrhythmic and defibrillatory studies. However the use of ECG reconstructed from optical mapping is seldom used and to date it has not been strictly validated. In this manuscript we present the first detailed validation and comparison of Optical Mapping ECG, or OM-ECG, with standard ECG recordings by calculating the electrostatic potential in space as a function of the voltage measured optically and describe the different approximations that can be used to obtain unipolar or bipolar ECG recordings. We found that in small/medium hearts, such as rabbits, leads that are aligned apex to base only require activation recording from one surface (anterior or posterior) for the OM-ECG to match the ECG while leads aligned left to right may require both an anterior and posterior optical mapping recording. The discrepancy between leads is due to symmetries in the ventricular activations. In the case of ischemic hearts where activations even-out more, the match between the OM-ECG and standard ECG may require only one surface recording for both left-right and base-apex leads. We believe that this methodology has two main and direct applications in the study of cardiac dynamics. The first is during studies of defibrillation where information after the shock may be crucial in the development of new strategies, OM-ECGs do not suffer the current artifacts of standard ECGs during shocks and can be calculated during the entire activation. We present examples in rabbit ventricles where even low amplitude pacing artifacts are captured by the ECG but do not appear in the OM-ECG. The second use of this technique is for reconstructions of intramural dynamics in larger hearts where differences between the ECG and OM-ECG obtained from anterior and posterior recordings can be used to derive the intramural activation.