H. Larry Scott

Modeling the lipid component of membranes

During the past several years, there have been a number of advances in the computational and theoretical modeling of lipid bilayer structural and dynamical properties. Molecular dynamics (MD) simulations have increased in length and time scales by about an order of magnitude. MD simulations continue to be applied to more complex systems, including mixed bilayers and bilayer self-assembly. A critical problem is bridging the gap between the still very small MD simulations and the time and length scales of experimental observations. Several new and promising techniques, which use atomic-level correlation and response functions from simulations as input to coarse-grained modeling, are being pursued.

Structure of Sphingomyelin Bilayers: A Simulation Study

We have carried out a molecular dynamics simulation of a hydrated 18:0 sphingomyelin lipid bilayer. The bilayer contained 1600 sphingomyelin (SM) molecules, and 50,592 water molecules. After construction and initial equilibration, the simulation was run for 3.8 ns at a constant temperature of 50 degrees C and a constant pressure of 1 atm. We present properties of the bilayer calculated from the simulation, and compare with experimental data and with properties of dipalmitoyl phosphatidylcholine (DPPC) bilayers. The SM bilayers are significantly more ordered and compact than DPPC bilayers at the same temperature. SM bilayers also exhibit significant intramolecular hydrogen bonding between phosphate ester oxygen and hydroxyl hydrogen atoms. This results in a decreased hydration in the polar region of the SM bilayer compared with DPPC. Since our simulation system is very large we have calculated the power spectrum of bilayer undulation and peristaltic modes, and we compare these data with similar calculations for DPPC bilayers. We find that the SM bilayer has significantly larger bending modulus and area compressibility compared to DPPC.

Multiscale simulations of heterogeneous model membranes

This review will focus on computer modeling aimed at providing insights into the existence, structure, size, and thermodynamic stability of localized domains in membranes of heterogeneous composition. Modeling the lateral organization within a membrane is problematic due to the relatively slow lateral diffusion rate for lipid molecules so that microsecond or longer time scales are needed to fully model the formation and stability of a raft in a membrane. Although atomistic simulations currently are not able to reach this scale, they can provide data on the intermolecular forces and correlations that are involved in lateral organization. These data can be used to define coarse grained models that are capable of predictions of lateral organization in membranes. In this paper, we review modeling efforts that use interaction data from MD simulations to construct coarse grained models for heterogeneous bilayers. In this review we will discuss MD simulations done with the aim of gaining the information needed to build accurate coarse-grained models. We will then review some of the coarse-graining work, emphasizing modeling that has resulted from or has a basis in atomistic simulations.

Nonintercalating Nanosubstrates Create Asymmetry between Bilayer Leaflets

The physical properties of lipid bilayers can be remodeled by a variety of environmental factors. Here we investigate using molecular dynamics simulations the specific effects of nanoscopic substrates or external contact points on lipid membranes. We expose palmitoyl-oleoyl phosphatidylcholine bilayers unilaterally and separately to various model nanosized substrates differing in surface hydroxyl densities. We find that a surface hydroxyl density as low as 10% is sufficient to keep the bilayer juxtaposed to the substrate. The bilayer interacts with the substrate indirectly through multiple layers of water molecules; however, despite such buffered interaction, the bilayers exhibit certain properties different from unsupported bilayers. The substrates modify transverse lipid fluctuations, charge density profiles, and lipid diffusion rates, although differently in the two leaflets, which creates an asymmetry between bilayer leaflets. Other properties that include lipid cross-sectional areas, component volumes, and order parameters are minimally affected. The extent of asymmetry that we observe between bilayer leaflets is well beyond what has been reported for bilayers adsorbed on infinite solid supports. This is perhaps because the bilayers are much closer to our nanosized finite supports than to infinite solid supports, resulting in a stronger support-bilayer electrostatic coupling. The exposure of membranes to nanoscopic contact points, therefore, cannot be considered as a simple linear interpolation between unsupported membranes and membranes supported on infinite supports. In the biological context, this suggests that the exposure of membranes to nonintercalating proteins, such as those belonging to the cytoskeleton, should not always be considered as passive nonconsequential interactions.

Effect of intrinsic and extrinsic factors on the simulated D‐band length of type I collagen

A signature feature of collagen is its axial periodicity visible in TEM as alternating dark and light bands. In mature, type I collagen, this repeating unit, D, is 67 nm long. This periodicity reflects an underlying packing of constituent triple‐helix polypeptide monomers wherein the dark bands represent gaps between axially adjacent monomers. This organization is visible distinctly in the microfibrillar model of collagen obtained from fiber diffraction. However, to date, no atomistic simulations of this diffraction model under zero‐stress conditions have reported a preservation of this structural feature. Such a demonstration is important as it provides the baseline to infer response functions of physiological stimuli. In contrast, simulations predict a considerable shrinkage of the D‐band (11–19%). Here we evaluate systemically the effect of several factors on D‐band shrinkage. Using force fields employed in previous studies we find that irrespective of the temperature/pressure coupling algorithms, assumed salt concentration or hydration level, and whether or not the monomers are cross‐linked, the D‐band shrinks considerably. This shrinkage is associated with the bending and widening of individual monomers, but employing a force field whose backbone dihedral energy landscape matches more closely with our computed CCSD(T) values produces a small D‐band shrinkage of < 3%. Since this force field also performs better against other experimental data, it appears that the large shrinkage observed in earlier simulations is a force‐field artifact. The residual shrinkage could be due to the absence of certain atomic‐level details, such as glycosylation sites, for which we do not yet have suitable data. Proteins 2015; 83:1800–1812.

Strategic Issues in Molecular Dynamics Simulations of Membranes

The heterogeneity associated with membrane systems poses a huge challenge for computer simulations of membrane dynamics and structure. Unlike proteins or nucleic acids with well-defined three-dimensional structures, membrane components such as lipid bilayers derive a vast majority of their properties and function from their fluid nature. This introduces the problem of setting up the correct bilayer model system for any realistic computer simulation. The model includes: choice of the system size; interatomic force fields; treatment of short and long-range interactions; and, most important, the macroscopic boundary conditions that best mimic experimental conditions. The simulation is thus an integral part of the model.

POPC Bilayers Supported on Nanoporous Substrates: Specific Effects of Silica-Type Surface Hydroxylation and Charge Density

Recent advances in nanotechnology bring to the forefront a new class of extrinsic constraints for remodeling lipid bilayers. In this next-generation technology, membranes are supported over nanoporous substrates. The nanometer-sized pores in the substrate are too small for bilayers to follow the substrate topology; consequently, the bilayers hang over the pores. Experiments demonstrate that nanoporous substrates remodel lipid bilayers differently from continuous substrates. The underlying molecular mechanisms, however, remain largely undetermined. Here we use molecular dynamics (MD) simulations to probe the effects of silica-type hydroxylation and charge densities on adsorbed palmitoyl-oleoylphosphatidylcholine (POPC) bilayers. We find that a 50% porous substrate decorated with a surface density of 4.6 hydroxyls/nm(2) adsorbs a POPC bilayer at a distance of 4.5 Å, a result consistent with neutron reflectivity experiments conducted on topologically similar silica constructs under highly acidic conditions. Although such an adsorption distance suggests that the interaction between the bilayer and the substrate will be buffered by water molecules, we find that the substrate does interact directly with the bilayer. The substrate modifies several properties of the bilayer-it dampens transverse lipid fluctuations, reduces lipid diffusion rates, and modifies transverse charge densities significantly. Additionally, it affects lipid properties differently in the two leaflets. Compared to substrates functionalized with sparser surface hydroxylation densities, this substrate adheres to bilayers at smaller distances and also remodels POPC more extensively, suggesting a direct correspondence between substrate hydrophilicity and membrane properties. A partial deprotonation of surface hydroxyls, as expected of a silica substrate under mildly acidic conditions, however, produces an inverse effect: it increases the substrate-bilayer distance, which we attribute to the formation of an electric double layer over the negatively charged substrate, and restores, at least partially, leaflet asymmetry and headgroup orientations. Overall, this study highlights the intrinsic complexity of lipid-substrate interactions and suggests the prospect of making two surface attributes-dipole densities and charge densities-work antagonistically toward remodeling lipid bilayer properties.

Atomistic and Coarse-Grained Computer Simulations of Raft-Like Lipid Mixtures

Computer modeling can provide insights into the existence, structure, size, and thermodynamic stability of localized raft-like regions in membranes. However, the challenges in the construction and simulation of accurate models of heterogeneous membranes are great. The primary obstacle in modeling the lateral organization within a membrane is the relatively slow lateral diffusion rate for lipid molecules. Microsecond or longer time-scales are needed to fully model the formation and stability of a raft in a membra ne. Atomistic simulations currently are not able to reach this scale, but they do provide quantitative information on the intermolecular forces and correlations that are involved in lateral organization. In this chapter, the steps needed to carry out and analyze atomistic simulations of hydrated lipid bilayers having heterogeneous composition are outlined. It is then shown how the data from a molecular dynamics simulation can be used to construct a coarse-grained model for the heterogeneous bilayer that can predict the lateral organization and stability of rafts at up to millisecond time-scales.

Chapter 10 Atomistic and Mean Field Simulations of Lateral Organization in Membranes

Publisher Summary This chapter provides an overview of molecular dynamics (MD) simulations of mixed lipid bilayer. The chapter shows how the data from MD simulations can be incorporated into a larger scale coarse-grained model that predicts lateral organization and phase properties over times and distances well beyond the reach of MD. The chapter discusses one of the most critical issues, the determination of the simulation force field parameters, describing new and highly accurate set of parameters developed. This phenomenon is studied by Pastor, MacKerell, and Klauda. Their effort is based on the inclusion of all hydrogen atoms on the lipids as well as the water, whereas the method discussed in the chapter uses a “united atom” approach for hydrogens on most lipid molecules. The chapter also describes the MD simulation of lipid bilayer of mixed composition and how the MD data from the mixed bilayer simulations can be used as input to construct a mean field-based coarse grained model that can serve as a predictive platform for the lateral organization of the membranes.