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Integral membrane protein function can be modulated by the host bilayer. Because biological membranes are diverse and nonuniform, we explore the consequences of lipid diversity using gramicidin A channels embedded in phosphatidylcholine (PC) bilayers composed of equimolar mixtures of di-oleoyl-PC and di-erucoyl-PC (dC 18:1 +dC 22:1 , respectively), di-palmitoleoyl-PC and di-nervonoyl-PC (dC 16:1 +dC 24:1 , respectively), and di-eicosenoyl-PC (pure dC 20:1 ), all of which have the same average bilayer chain length. Single-channel lifetime experiments, molecular dynamics simulations, and a simple lipid compression model are used in tandem to gain insight into lipid redistribution around the channel, which partially alleviates the bilayer deformation energy associated with channel formation. The average single-channel lifetimes in the two-component bilayers (95 ± 10 ms for dC 18:1 +dC 22:1 and 195 ± 20 ms for dC 16:1 +dC 24:1 ) were increased relative to the single-component dC 20:1 control bilayer (65 ± 10 ms), implying lipid redistribution. Using a theoretical treatment of thickness-dependent changes in channel lifetimes, the effective local enrichment of lipids around the channel was estimated to be 58 ± 4% dC 18:1 and 66 ± 2% dC 16:1 in the dC 18:1 +dC 22:1 and dC 16:1 +dC 24:1 bilayers, respectively. 3.5-μs molecular dynamics simulations show 66 ± 2% dC 16:1 in the first lipid shell around the channel in the dC 16:1 +dC 24:1 bilayer, but no significant redistribution (50 ± 4% dC 18:1 ) in the dC 18:1 +dC 22:1 bilayer; these simulated values are within the 95% confidence intervals of the experimental averages. The strong preference for the better matching lipid (dC 16:1 ) near the channel in the dC 16:1 +dC 24:1 mixture and lesser redistribution in the dC 18:1 +dC 22:1 mixture can be explained by the energetic cost associated with compressing the lipids to match the channel's hydrophobic length., (Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

All-atom simulation data are presented for ternary mixtures of palmitoyl sphingomyelin (PSM), cholesterol, and either palmitoyl oleoyl phosphatidyl choline or dioleoyl phosphatidyl choline (DOPC). For comparison, data for a mixture of dipalmitoyl phosphatidyl choline (DPPC), cholesterol, and DOPC are also presented. Compositions corresponding to the liquid-ordered phase, the liquid-disordered phase, and coexistence of the two phases are simulated for each mixture. Within the liquid-ordered phase, cholesterol is preferentially solvated by DOPC if it is available, but if DOPC is replaced by POPC, cholesterol is preferentially solvated by PSM. In the DPPC mixtures, cholesterol interacts preferentially with the saturated chains via its smooth face, whereas in the PSM mixtures, cholesterol interacts preferentially with PSM via its rough face. Interactions between cholesterol and PSM have a very particular character: hydrogen bonding between cholesterol and the amide of PSM rotates the tilt of the amide plane, which primes it for more robust hydrogen bonding with other PSM. Cholesterol-PSM hydrogen bonding also locally modifies the hexagonal packing of hydrocarbon chains in the liquid-ordered phase of PSM mixtures., (Copyright © 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

α-Synuclein (α-syn) membrane interactions are implicated in the pathogenesis of Parkinson's disease. Fluorescence and neutron reflectometry (NR) measurements reveal that α-syn penetrates ∼9-14 Å into the outer leaflet of the bilayer, with a substantial portion of the membrane-bound polypeptide extending into the aqueous solvent. For the first time, to our knowledge, we used NR to obtain direct quantitative evidence of α-syn-induced membrane thinning. To examine the effect of specific residues on membrane penetration depths, we used a series of W4-containing N-terminal peptides. We identified that the first 15 residues (P15) nearly recapitulate the features of the full-length protein (i.e., partition constants, molecular mobility, and insertion of the W4 side chain into the bilayer), and found that as few as the first four N-terminal residues are sufficient for vesicle binding. Although at least one imperfect amphipathic repeat sequence (KAKEGV) is required for α-helical formation, secondary structural formation has little effect on membrane affinity. To develop an N-terminal α-syn model for bilayer interactions, we performed molecular-dynamics simulations of the P15 peptide submerged in a bilayer. The simulation results are highly consistent with experimental data indicating a broad low-energy region (8.5-14.5 Å) for W4 insertion., (Copyright © 2012 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Proper simulation of dynamic properties, including molecular diffusion, is an important goal of empirical force fields. However, the widely used TIP3P water model does not reproduce the experimental viscosity of water. Consequently, scaling of simulated diffusion constants of solutes in aqueous solutions is required to effectively compare them with experiment. It is proposed that scaling by the ratio of viscosities of model and real water is appropriate in the regime where the concentration dependence of simulated and experimental solution viscosities is parallel. With this ansatz, viscosity scaling can be carried out for glucose and trehalose up to 20 wt % for simulations carried out with the CHARMM additive carbohydrate force field C35 and TIP3P water; above this value, the concentration dependence of simulated viscosities lags that of experiment, and scaling is not advised. Scaled translational diffusion constants for glucose and the disaccharides trehalose, maltose, and melibiose at low concentration agree nearly quantitatively with experiment, as do NMR (13)C T(1)'s for glucose, trehalose, and maltose; these results support the use of C35 for simulations of sugar transport properties at low concentration. At high concentrations the scaled diffusion constants for glucose and trehalose underestimate and overestimate experiment, respectively. Hydrodynamic bead model calculations indicate a hydration level of approximately 1 water/hydroxyl for glucose. Patterns for the disaccharides are more complicated, though trehalose binds 0.5 to 1 more water than does maltose depending on the analysis.

A revision (C35r) to the CHARMM ether force field is shown to reproduce experimentally observed conformational populations of dimethoxyethane. Molecular dynamics simulations of 9, 18, 27, and 36-mers of polyethylene oxide (PEO) and 27-mers of polyethylene glycol (PEG) in water based on C35r yield a persistence length lambda = 3.7 A, in quantitative agreement with experimentally obtained values of 3.7 A for PEO and 3.8 A for PEG; agreement with experimental values for hydrodynamic radii of comparably sized PEG is also excellent. The exponent upsilon relating the radius of gyration and molecular weight (R(g) proportional, variantM(w)(upsilon)) of PEO from the simulations equals 0.515 +/- 0.023, consistent with experimental observations that low molecular weight PEG behaves as an ideal chain. The shape anisotropy of hydrated PEO is 2.59:1.44:1.00. The dimension of the middle length for each of the polymers nearly equals the hydrodynamic radius R(h)obtained from diffusion measurements in solution. This explains the correspondence of R(h) and R(p), the pore radius of membrane channels: a polymer such as PEG diffuses with its long axis parallel to the membrane channel, and passes through the channel without substantial distortion.

Molecular dynamics simulations and (31)P-NMR spin-lattice (R(1)) relaxation rates from 0.022 to 21.1 T of fluid phase dipalmitoylphosphatidylcholine bilayers are compared. Agreement between experiment and direct prediction from simulation indicates that the dominant slow relaxation (correlation) times of the dipolar and chemical shift anisotropy spin-lattice relaxation are approximately 10 ns and 3 ns, respectively. Overall reorientation of the lipid body, consisting of the phosphorus, glycerol, and acyl chains, is well described within a rigid-body model. Wobble, with D(perpendicular)= 1-2 x 10(8) s(-1), is the primary component of the 10 ns relaxation; this timescale is consistent with the tumbling of a lipid-sized cylinder in a medium with the viscosity of liquid hexadecane. The value for D(parallel), the diffusion constant for rotation about the long axis of the lipid body, is difficult to determine precisely because of averaging by fast motions and wobble; it is tentatively estimated to be 1 x 10(7) s(-1). The resulting D(parallel)/D( perpendicular) approximately 0.1 implies that axial rotation is strongly modulated by interactions at the lipid/water interface. Rigid-body modeling and potential of mean force evaluations show that the choline group is relatively uncoupled from the rest of the lipid. This is consistent with the ratio of chemical shift anisotropy and dipolar correlation times reported here and the previous observations that (31)P-NMR lineshapes are axially symmetric even in the gel phase of dipalmitoylphosphatidylcholine.

A range of ab initio calculations were carried out on the axial and equatorial anomers of the model carbohydrate 2-ethoxy tetrahydropyran to evaluate the level of theory required to accurately evaluate the glycosyl dihedral angle and the anomeric ratio. Vacuum CCSD(T)/CBS extrapolations at the global minimum yield DeltaE = E(equatorial) - E(axial) = 1.42 kcal/mol. When corrected for solvent (by the IEFPCM model), zero-point vibrations and entropy, DeltaG(298) = 0.49 kcal/mol, in excellent agreement with the experimental value of 0.47 +/- 0.3 kcal/mol. A new additivity scheme, the layered composite method (LCM), yields DeltaE to within 0.1 kcal/mol of the CCSD(T)/CBS result at a fraction of the computer requirements. Anomeric ratios and one-dimensional torsional surfaces generated by LCM and the even more efficient MP2/cc-pVTZ level of theory are in excellent agreement, indicating that the latter is suitable for force-field parameterization of carbohydrates. Hartree-Fock and density functional theory differ from CCSD(T)/CBS for DeltaE by approximately 1 kcal/mol; they show similar deviations in torsional surfaces evaluated from LCM. A comparison of vacuum and solvent-corrected one- and two-dimensional torsional surfaces indicates the equatorial form of 2-ethoxy tetrahydropyran is more sensitive to solvent than the axial.

Surface tensions evaluated from molecular dynamics simulations of fully hydrated dipalmitoylphosphatidylcholine bilayers and monolayers at surface areas/lipid of 54, 64, and 80 A2 are uniformly lowered 4-8 dyn/cm upon addition of trehalose in a 1:2 trehalose/lipid ratio. Constant surface tension simulations of bilayers yield the complementary result: an increase in surface area consistent with the surface pressure-surface area (pi-A) isotherms. Hydrogen bonding by trehalose, replacement of waters in the headgroup region, and modulation of the dipole potential are all similar in bilayers and monolayers at the same surface area. These results strongly support the assumption that experimental measurements on the interactions of surface active components such as trehalose with monolayers can yield quantitative insight to their effects on bilayers. The simulations also indicate that the 20-30 dyn/cm difference in surface tension of the bilayer leaflet and monolayer arises from differences in the chain regions, not the headgroup/water interfaces.

The preferred conformations and conformational flexibilities of the trisaccharides alpha-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)-alpha-D-Glcp-OMe (I) and alpha-D-Glcp-(1-->3)[beta-D-Glcp-(1-->4)]-alpha-D-Glcp-OMe (II) in aqueous solution were determined using nuclear magnetic resonance (NMR) spectroscopy, molecular dynamics (MD) and Langevin dynamics (LD) simulations, and hydrodynamics calculations. Both trisaccharides have a vicinal substitution pattern in which long range (nonsequential) interactions may play an important role. LD simulation at 600 K indicated that the all-syn conformation predominated, though other conformations were apparent. NOE data and MD and LD simulations at 298 K all indicated that trisaccharide I is a single all-syn conformer in solution. Given that previous studies showed evidence of anti-conformers in beta-D-Glcp-(1-->2)-beta-D-Glcp-(1-->3)-alpha-D-Glcp-OMe, this result provides an example of how changing the anomeric configuration of one residue from beta to alpha can make an oligosaccharide more rigid. Discrepancies in inter-ring distances obtained by experiment and by simulation of the all-syn conformer suggest the presence of an anti-psi conformation at the beta-(1-->4)-linkage for II. A combined analysis of measured and calculated translational diffusion constants and (13)C T(1) relaxation times yield order parameters of 0.9 for each trisaccharide. This implies that any interconversion among conformations is significantly slower than tumbling. Anisotropies of approximately 1.6 and 1.3 calculated for I and II, respectively, are consistent with the observed relatively flat T(1) profiles because the tumbling is not in the motional narrowing regime.