The plasma membrane, which encapsulates human cells, is composed of a complex mixture of lipids and embedded proteins. Emerging knowledge points towards the lipids as having a regulating role in protein function. Furthermore, insight from protein crystallography has revealed several different types of lipids intimately bound to membrane proteins and peptides, hereby possibly pointing to a site of action for the observed regulation. Cholesterol is among the lipid membrane constituents most often observed to be co-crystallized with membrane proteins, and the cholesterol levels in cell membranes have been found to play an essential role in health and disease. Remarkably little is known about the mechanism of lipid regulation of membrane protein function in health as well as in disease. Herein, we review molecular dynamics simulation studies aimed at investigating the effect of cholesterol on membrane protein and peptide properties. This article is part of a Special Issue entitled: Lipid-protein interactions.

A definition that equates a hydrogen bond topologically with a local energy well in the potential energy surface is used to study the structure and dynamics of liquid water. We demonstrate the robustness of this hydrogen-bond definition versus the many other definitions which use fixed, arbitrary parameters, do not account for variable molecular environments, and cannot effectively resolve transition states. Our topology definition unambiguously shows that most water molecules are double acceptors but sizable proportions are single or triple acceptors. Almost all hydrogens are found to take part in hydrogen bonds. Broken hydrogen bonds only form when two molecules try to form two hydrogen bonds between them. The double acceptors have tetrahedral geometry, lower potential energy, entropy, and density, and slower dynamics. The single and triple acceptors have trigonal and trigonal bipyramidal geometry and when considered together have higher density, potential energy, and entropy, faster dynamics, and a tendency to cluster. These calculations use an extended theory for the entropy of liquid water that takes into account the variable number of hydrogen bonds. Hydrogen-bond switching is shown to depend explicitly on the variable number of hydrogen bonds accepted and the presence of interstitial water molecules. Transition state theory indicates that the switching of hydrogen bonds is a mildly activated process, requiring only a moderate distortion of hydrogen bonds. Three main types of switching events are observed depending on whether the donor and acceptor are already sharing a hydrogen bond. The switch may proceed with no intermediate or via a bifurcated-oxygen or cyclic dimer, both of which have a broken hydrogen bond and symmetric and asymmetric forms. Switching is found to be strongly coupled to whole-molecule vibration, particularly for the more mobile single and triple acceptors. Our analysis suggests that even though water is heterogeneous in terms of the number of hydrogen bonds, the coupling between neighbors on various length and time scales brings about greater continuity in its properties.

An equation for the chemical potential of a dilute aqueous solution of noble gases is derived in terms of energies, force and torque magnitudes, and solute and water coordination numbers, quantities which are all measured from an equilibrium molecular dynamics simulation. Also derived are equations for the Gibbs free energy, enthalpy and entropy of hydration for the Henry's law process, the Ostwald process, and a third proposed process going from an arbitrary concentration in the gas phase to the equivalent mole fraction in aqueous solution which has simpler expressions for the enthalpy and entropy changes. Good agreement with experimental hydration free energies is obtained in the TIP4P and SPC/E water models although the solute's force field appears to affect the enthalpies and entropies obtained. In contrast to other methods, the approach gives a complete breakdown of the entropy for every degree of freedom and makes possible a direct structural interpretation of the well-known entropy loss accompanying the hydrophobic hydration of small non-polar molecules under ambient conditions. The noble-gas solutes experience only a small reduction in their vibrational entropy, with larger solutes experiencing a greater loss. The vibrational and librational entropy components of water actually increase but only marginally, negating any idea of water confinement. The term that contributes the most to the hydrophobic entropy loss is found to be water's orientational term which quantifies the number of orientational minima per water molecule and how many ways the whole hydrogen-bond network can form. These findings help resolve contradictory deductions from experiments that water structure around non-polar solutes is similar to bulk water in some ways but different in others. That the entropy loss lies in water's rotational entropy contrasts with other claims that it largely lies in water's translational entropy, but this apparent discrepancy arises because of different coordinate definitions and reference frames used to define the entropy terms.

Two theoretical formulations are proposed and compared for the loss of translational and rotational entropy upon protein-ligand binding in water. The two theories share the same approach to evaluate the translational and rotational entropy of the ligand when bound. The potential of the bound ligand is modeled by six harmonic oscillators that are parametrized from the force and torque magnitudes measured in a molecular dynamics simulation, yielding vibrational and librational entropies. In the aqueous phase, the theories differ because there is no unique way to assign the total entropy to molecules in solution. In one approach, the ligand is allowed unrestricted access to the full solution volume at the standard concentration and is assigned the same translational and rotational entropy as if it were an ideal gas. We term this a "molecule-frame" (MF) theory because it considers configurational space in the reference frame of the molecule of interest. The entropy of the solvent is penalized because it is excluded from the molecule's volume. In the second theory, all molecules including the solvent are confined by their neighbors in mean-field configurational volumes. This we term a "system-frame" (SF) theory because the configurational space available to all molecules is considered in the reference frame of the whole system. Molecules have vibrational and librational entropy in the same way as they do when bound. In addition, the discrete size of the solvent molecules quantizes the configurational space into an effective number of minima according to the solute molecule's standard concentration and the mean volume of a solvent molecule. This leads to the cratic entropy expressed in terms of the solute molecule's mole fraction. The equivalent number of minima in rotational space depends on both the solute molecule's volume and the solvent molecule's volume. This leads to an equation for the orientational entropy based on the proposed concept of "angle fraction". The MF and SF theories are applied to calculate the translational and rotational entropy losses involved in the formation of six different protein-ligand complexes, in two of which the ligand is water. The MF entropy losses range from -80 to -142 J K(-1) mol(-1) for ligands at the 1 M standard-state concentration and from -52 to -63 J K(-1) mol(-1) for water at the 55.6 M standard-state concentration. They depend logarithmically on both the number and strength of interactions between the ligand and protein through the forces and torques. This is observed to lead to moderate dependencies on the ligands' moments of inertia and masses. The SF entropy losses are smaller and range from -50 to -75 J K(-1) mol(-1) for ligands at the 1 M standard-state concentration and from 0 to -12 J K(-1) mol(-1) for water. They depend logarithmically on the ligand solvent's molecular volume and weakly on the relative strengths of the ligand's interactions with the protein and water. The cratic entropy loss in water at the standard concentration is constant and is also demonstrat...

There is a considerable disagreement about the extent to which solutes perturb water structure. On the one hand, studies that analyse structure directly only show local structuring in a solute's first and possibly second hydration shells. On the other hand, thermodynamic and kinetic data imply indirectly that structuring occurs much further away. Here, the hydrogen-bond structure of water around halide anions, alkali cations, noble-gas solutes, and at the vapor-water interface is examined using molecular dynamics simulations. In addition to the expected perturbation in the first hydration shell, deviations from bulk behavior are observed at longer range in the rest of the simulation box. In particular, at the longer range, there is an excess of acceptors around halide anions, an excess of donors around alkali cations, weakly enhanced tetrahedrality and an oscillating excess and deficiency of donors and acceptors around noble-gas solutes, and enhanced tetrahedrality at the vapor-water interface. The structuring compensates for the short-range perturbation in water-water hydrogen bonds induced by the solute. Rather than being confined close to the solute, it is spread over as many water molecules as possible, presumably to minimize the perturbation to each water molecule.