Understanding how different classes of molecules move across biological membranes is a prerequisite to predicting a solute's permeation rate, which is a critical factor in the fields of drug design and pharmacology. We use biased molecular dynamics computer simulations to calculate and compare the free energy profiles of translocation of several small molecules across 1,2-dioleoyl- sn-glycero-3-phosphocholine (DOPC) lipid bilayers as a first step toward determining the most efficient method for free energy calculations. We study the translocation of arginine, a sodium ion, alanine, and a single water molecule using the metadynamics, umbrella sampling, and replica exchange umbrella sampling techniques. Within the fixed lengths of our simulations, we find that all methods produce similar results for charge-neutral permeants, but not for polar or positively charged molecules. We identify the long relaxation time scale of electrostatic interactions between lipid headgroups and the solute to be the principal cause of this difference and show that this slow process can lead to an erroneous dependence of computed free energy profiles on the initial system configuration. We demonstrate the use of committor analysis to validate the proper sampling of the presumed transition state, which in our simulations is achieved only in replica exchange calculations. On the basis of these results we provide some useful guidance to perform and evaluate free energy calculations of membrane permeation.

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Amphiphilic molecules can alter the wettability of soil minerals. To determine how the headgroup chemistry of amphiphiles determines these effects, we investigate a system of the clay montmorillonite with long-chain phospholipids. We use phosphatidylglycerol (PG) phospholipids to contrast with our previous work using phosphatidylethanolamine (PE) lipids. Zwitterionic PE lipids can sorb to the negatively charged montmorillonite surface, whereas negatively charged PG lipids cannot. Employing a suite of techniques from molecular dynamics, atomic force microscopy, fluorescence microscopy, and contact angle measurements, we define sample characteristics from molecular-scale structure to the macroscopic wettability. We find that PG lipids do not significantly alter montmorillonite wetting characteristics, such as the contact angle, flow viscosity, and the characteristic time scale for droplet imbibition. On comparing PE and PG lipid/clay films, we find that, among the phospholipids compared, they must have three characteristics to change clay/lipid film wettability: they must bind to the mineral surface, be solid at room temperature, and have a relatively continuous distribution throughout the film.

Intrinsically disordered proteins (IDPs) are a class of proteins that lack a unique native three-dimensional structure. Molecular dynamics (MD) is an invaluable method to study the dynamics of folded proteins. However, there have been challenges in its application to simulating IDPs. One of these challenges is the need to sample a vast number of structural conformations. To help overcome this challenge, one of the methods that was introduced is the temperature replica exchange (TRE) algorithm. This method uses a random walk in temperature space to help overcome energy barriers. However, this method can require vast computing resources and the efficiency of the TRE algorithm is not well characterized. We use a variant of Hamiltonian replica exchange (HRE), which instead of temperature uses the scaling of the Lennard-Jones protein-water interactions. In conducting the algorithm in this manner, the computational requirements are reduced compared to TRE. Here, we used MD simulations on an IDP system to compare the sampling efficiency between these sampling algorithms. We tested this algorithm on the RS1 region of the serine/arginine-rich splicing factor 1; an IDP with many consecutive repeating RS residues. In on-going work, we are comparing the computational efficiency of the HRE algorithm to TRE, conventional MD simulation, as well as other HRE algorithms.

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