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Register a new userImpact of Cholesterol on Voids in Phospholipid Membranes
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Free volume pockets or voids are important to many biological processes in cell membranes. Free volume fluctuations are a prerequisite for diffusion of lipids and other macromolecules in lipid bilayers. Permeation of small solutes across a membrane, as well as diffusion of solutes in the membrane interior are further examples of phenomena where voids and their properties play a central role. Cholesterol has been suggested to change the structure and function of membranes by altering their free volume properties. We study the effect of cholesterol on the properties of voids in dipalmitoylphosphatidylcholine (DPPC) bilayers by means of atomistic molecular dynamics simulations. We find that an increasing cholesterol concentration reduces the total amount of free volume in a bilayer. The effect of cholesterol on individual voids is most prominent in the region where the steroid ring structures of cholesterol molecules are located. Here a growing cholesterol content reduces the number of voids, completely removing voids of the size of a cholesterol molecule. The voids also become more elongated. The broad orientational distribution of voids observed in pure DPPC is, with a 30% molar concentration of cholesterol, replaced by a distribution where orientation along the bilayer normal is favored. Our results suggest that instead of being uniformly distributed to the whole bilayer, these effects are localized to the close vicinity of cholesterol molecules.
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We employ 100 ns molecular dynamics simulations to study the influence of cholesterol on structural and dynamic properties of dipalmitoylphosphatidylcholine (DPPC) bilayers in the fluid phase. The effects of the cholesterol content on the bilayer structure are considered by varying the cholesterol concentration between 0 and 50%. We concentrate on the free area in the membrane and investigate quantities that are likely to be affected by changes in the free area and free volume properties. It is found that cholesterol has a strong impact on the free area properties of the bilayer. The changes in the amount of free area are shown to be intimately related to alterations in molecular packing, ordering of phospholipid tails, and compressibility. Further, the behavior of the lateral diffusion of both DPPC and cholesterol molecules with an increasing amount of cholesterol can in part be understood in terms of free area. Summarizing, our results highlight the central role of free area in comprehending the structural and dynamic properties of membranes containing cholesterol.
Water provides the driving force for the assembly and stability of many cellular components. Despite its impact on biological functions, a nanoscale understanding of the relationship between its structure and dynamics under soft confinement has remained elusive. As expected, water in contact with biological membranes recovers its bulk density and dynamics at $sim 1$ nm from phospholipid headgroups but surprisingly enhances its intermediate-range order (IRO) over a distance, at least, twice as large. Here, we explore how the IRO is related to the waters hydrogen bond network (HBN) and its coordination defects. We characterize the increased IRO by an alteration of the HBN up to more than eight coordination shells of hydration water. The HBN analysis emphasizes the existence of a bound-unbound water interface at $sim 0.8$ nm from the membrane. The unbound water has a distribution of defects intermediate between bound and bulk water, but with density and dynamics similar to bulk, while bound water has reduced thermal energy and much more HBN defects than low-temperature water. This observation could be fundamental for developing nanoscale models of biological interactions and for understanding how alteration of the water structure and topology, for example, due to changes in extracellular ions concentration, could affect diseases and signaling. More generally, it gives us a different perspective to study nanoconfined water.
We report a high energy-resolution neutron backscattering study, combined with in-situ diffraction, to investigate slow molecular motions on nanosecond time scales in the fluid phase of phospholipid bilayers of 1,2-dimyristoyl-sn-glycero-3-phoshatidylcholine (DMPC) and DMPC/40% cholesterol (wt/wt). A cooperative structural relaxation process was observed. From the in-plane scattering vector dependence of the relaxation rates in hydrogenated and deuterated samples, combined with results from a 0.1 microsecond long all atom molecular dynamics simulation, it is concluded that correlated dynamics in lipid membranes occurs over several lipid distances, spanning a time interval from pico- to nanoseconds.
We present the first inelastic neutron scattering study of the short wavelength dynamics in a phospholipid bilayer. We show that inelastic neutron scattering using a triple-axis spectrometer at the high flux reactor of the ILL yields the necessary resolution and signal to determine the dynamics of model membranes. The results can quantitatively be compared to recent Molecular Dynamics simulations. Reflectivity, in-plane correlations and the corresponding dynamics can be measured simultaneously to gain a maximum amount of information. With this method, dispersion relations can be measured with a high energy resolution. Structure and dynamics in phospholipid bilayers, and the relation between them, can be studied on a molecular length scale.
Area per molecule in a DPPC-Cholesterol bilayers depends non-linearly on the cholesterol concentration. Using flexible strings model of lipid membranes we calculate area per molecule in DPPC-Cholesterol mixtures in the biologically relevant concentrations range. Few parameters of the model are optimized for a perfect agreement with the area per lipid data available from molecular dynamics simulations. Lateral pressure at the hydrophilic interface, {gamma}, is taken to be proportional to the cholesterol concentration. Non-linearity arises as a consequence of the non-linear dependence of thermodynamical equilibrium area of molecules on {gamma}. DPPC lipid is modeled as flexible string of finite thickness and a given bending rigidity, while cholesterol molecule is modeled as rigid rod with finite thickness and infinite rigidity. Using parameters fitted to reproduce area per molecule dependence on cholesterol concentration, we had further calculated our model predictions for the NMR order parameter of DPPC lipid chains and coefficient of thermal area expansion. The microscopic nature of the model allows to consider a broad range of thermodynamic phenomena.
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