Carbohydrate-derived amphiphilic macromolecules: a biophysical structural characterization and analysis of binding behaviors to model membranes.

The design and synthesis of enhanced membrane-intercalating biomaterials for drug delivery or vascular membrane targeting is currently challenged by the lack of screening and prediction tools. The present work demonstrates the generation of a Quantitative Structural Activity Relationship model (QSAR) to make a priori predictions. Amphiphilic macromolecules (AMs) "stealth lipids" built on aldaric and uronic acids frameworks attached to poly(ethylene glycol) (PEG) polymer tails were developed to form self-assembling micelles. In the present study, a defined set of novel AM structures were investigated in terms of their binding to lipid membrane bilayers using Quartz Crystal Microbalance with Dissipation (QCM-D) experiments coupled with computational coarse-grained molecular dynamics (CG MD) and all-atom MD (AA MD) simulations. The CG MD simulations capture the insertion dynamics of the AM lipophilic backbones into the lipid bilayer with the PEGylated tail directed into bulk water. QCM-D measurements with Voigt viscoelastic model analysis enabled the quantitation of the mass gain and rate of interaction between the AM and the lipid bilayer surface. Thus, this study yielded insights about variations in the functional activity of AM materials with minute compositional or stereochemical differences based on membrane binding, which has translational potential for transplanting these materials in vivo. More broadly, it demonstrates an integrated computational-experimental approach, which can offer a promising strategy for the in silico design and screening of therapeutic candidate materials

EXPERIMENTAL AND MOLECULAR DYNAMICS SIMULATION STUDIES OF PARTITIONING AND TRANSPORT ACROSS LIPID BILAYER MEMBRANES

Most drugs undergo passive transport during absorption and distribution in the body. It is desirable to predict passive permeation of future drug candidates in order to increase the productivity of the drug discovery process. Unlike drug-receptor interactions, there is no receptor map for passive permeability because the process of transport across the lipid bilayer involves multiple mechanisms. This work intends to increase the understanding of permeation of drug-like molecules through lipid bilayers. Drug molecules in solution typically form various species due to ionization, complexation, etc. Therefore, species specific properties must be obtained to bridge the experiment and simulations. Due to the volume contrast between intra- and extravesicular compartments of liposomes, minor perturbations in ionic and binding equilibria become significant contributors to transport rates. Using tyramine as a model amine, quantitative numerical models were developed to determine intrinsic permeability coefficients. The microscopic ionization and binding constants needed for this were independently measured. The partition coefficient in 1,9-decadiene was measured for a series of compounds as a quantitative surrogate for the partitioning into the hydrocarbon region of the bilayer. These studies uncovered an apparent long-range interaction between the two polar substituents that caused deviations in the microscopic pKa values and partition coefficient of tyramine from the expected values. Additionally the partition coefficients in the preferred binding region of the bilayer were also measured by equilibrium uptake into liposomes. All-atom molecular dynamics simulations of lipid bilayers containing tyramine, 4- ethylphenol, or phenylethylamine provided free energies of transfer of these solutes from water to various locations on the transport path. The experimentally measured partition coefficients were consistent with the free energy profiles in showing the barrier in the hydrocarbon region and preferred binding region near the interface. The substituent contributions to these free energies were also quantitatively consistent between the experiments and simulations. Specific interactions between solutes and the bilayer suggest that amphiphiles are likely to show preferred binding in the head group region and that the most of hydrogen bonds involving solutes located inside the bilayer are with water molecules. Solute re-orientation inside the bilayer lowers the partitioning barrier by allowing favorable interactions

Molecular Dynamics Simulation Studies of Interaction of Amphiphilic Molecules with Lipid Bilayers

We use molecular dynamics simulations to investigate the behavior of various amphiphilic molecules in aqueous solutions in the presence of vitamin E or lipid bilayers. Our research studies focus on two molecular systems. First, we investigate the effect of DMSO on structural properties of DMPC bilayers and calculate bilayers permeability coefficients for both water and DMSO molecules at low DMSO concentration. The simulations show that the increase of DMSO concentration in solution leads to an increase of the permeability of water through the bilayers. The permeability increase might explain the unusual ability of DMSO, even at relatively low concentrations, to allow fast relaxation of osmotic pressure imbalance present during cryopreservation protocols. The second part of our research aims at the development of a molecular-level understanding of solubilization of vitamin E by bile salts and its adsorption and positioning into cell membranes. Specifically, in a sequence of MD simulations, we investigate the aggregation behavior and interaction of cholate (CHD) and glycocholate (GCH) with oleic acid and vitamin E and adsorption, positioning, and aggregation of vitamin E molecules inside a DMPC lipid bilayer. The simulations show that at concentrations above critical micelle concentration the bile salt molecules aggregate spontaneously into small ablate micelles in just a few nanoseconds. The oblate shape is favored by bile salts unique molecular structure. The study of interaction of bile salts with oleic acid show that oleic acid molecules are solubilized spontaneously into preformed bile salt micelles. The MD study of interaction of bile salts with vitamin E show that preformed bile salt micelles are spontaneously adsorbed at the vitamin E-water interface; adsorption process that leads to important changes of interfacial energy, surface tension, and interface structure. In addition, our MD simulations demonstrate that a-tocopherol incorporates spontaneously into DMPC lipid bilayers and accumulates in a relatively narrow region, just below the membrane-water interface. This is of great significance because even if its concentration in membranes is relatively low, the spatial confinement of a-tocopherol inside the bilayer greatly enhances its concentration in this vital region, thus increasing their importance for in vivo biological activities including oxidative stress defense

Molecular dynamics simulations of biological membranes in the presence of cryoprotectants

Cryopreservation is a process that is characterized by the transport of water and cryoprotectants through the cell membrane. This phenomenon has been studied in extensive detail at the macroscopic (µm) scale but in a somewhat more limited fashion at the microscopic (nm) scale. In this study we develop several lipid bilayer models to approximate a cell membrane (nm) and present the effect of several different cryoprotectants on the structural characteristics of these lipid bilayers using molecular dynamic simulations. The lipid bilayer models included dipalmitoylphosphatidylcholine (DPPC), dimyristoylphosphatidylcholine (DMPC) and palmitoyleylphosphatidylcholine (POPC) while the cryoprotectants included methanol and dimethylsulfoxide (DMSO). The molecular dynamic investigations suggests that the presence of methanol and DMSO has a significant effect on several structural properties of the lipid bilayers, including the area per lipid, mass density of nitrogen and phosphorus atoms in the lipid heads, water ordering near the bilayer and the radial distribution functions between several atoms in the lipid heads. Taken together, these results show that the presence of methanol and DMSO significantly decreases the bilayer thickness and suggests that the bilayers become more permeable to small molecules in their presence

USSR Space Life Sciences Digest, issue 32

This is the thirty-second issue of NASA's USSR Space Life Sciences Digest. It contains abstracts of 34 journal or conference papers published in Russian and of 4 Soviet monographs. Selected abstracts are illustrated with figures and tables from the original. The abstracts in this issue have been identified as relevant to 18 areas of space biology and medicine. These areas include: adaptation, aviation medicine, biological rhythms, biospherics, cardiovascular and respiratory systems, developmental biology, exobiology, habitability and environmental effects, human performance, hematology, mathematical models, metabolism, microbiology, musculoskeletal system, neurophysiology, operational medicine, and reproductive system

Understanding the role of lipids in signaling through atomistic and multiscale simulations of cell membranes

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