Maria Maddalena Sperotto

Theoretical analysis of protein organization in lipid membranes.

The fundamental physical principles of the lateral organization of trans-membrane proteins and peptides as well as peripheral membrane proteins and enzymes are considered from the point of view of the lipid-bilayer membrane, its structure, dynamics, and cooperative phenomena. Based on a variety of theoretical considerations and model calculations, the nature of lipid-protein interactions is considered both for a single protein and an assembly of proteins that can lead to aggregation and protein crystallization in the plane of the membrane. Phenomena discussed include lipid sorting and selectivity at protein surfaces, protein-lipid phase equilibria, lipid-mediated protein-protein interactions, wetting and capillary condensation as means of protein organization, mechanisms of two-dimensional protein crystallization, as well as non-equilibrium organization of active proteins in membranes. The theoretical findings are compared with a variety of experimental data.

Monte Carlo simulation studies of lipid order parameter profiles near integral membrane proteins

Monte Carlo simulation techniques have been applied to a statistical mechanical lattice model in order to study the coherence length for the spatial fluctuations of the lipid order parameter profiles around integral membrane proteins in dipalmitoyl phosphatidylcholine bilayers. The model, which provides a detailed description of the pure lipid bilayer main transition, incorporates hydrophobic matching between the lipid and protein hydrophobic thicknesses as a major contribution to the lipid-protein interactions in lipid membranes. The model is studied at low protein-to-lipid ratios. The temperature dependence of the coherence length is found to have a dramatic peak at the phase transition temperature. The dependence on protein circumference as well as hydrophobic length is determined and it is concluded that in some cases the coherence length is much longer than previously anticipated. The long coherence length provides a mechanism for indirect lipid-mediated protein-protein long-range attraction and hence plays an important role in regulating protein segregation.

Dependence of lipid membrane phase transition temperature on the mismatch of protein and lipid hydrophobic thickness

A two-component solution theory is studied which incorporates hydrophobic matching as a major contribution to the lipid-protein interactions in biological membranes. A special geometrical constraint has been discovered which has important implications for the quantitative interpretation of physical effects to lipid-protein interactions. The theory has an advantage over conventional Landau-type phenomenological descriptions in that it accounts for phase separation. A certain class of experimental systems, photosynthetic reaction centre and antenna proteins reconstituted into synthetic lipid membranes of different hydrophobic thicknesses, are considered with a view to determining the parameters of the theory. The theoretical predictions are found to be in good agreement with experimental measurements of shifts in the phase transition temperature.

Lipid enrichment and selectivity of integral membrane proteins in two-component lipid bilayers

A model recently used to study lipid-protein interactions in one-component lipid bilayers (Sperotto and Mouritsen, 1991 a, b) has been extended in order to include two different lipid species characterized by different acyl-chain lengths. The model, which is a statistical mechanical lattice model, assumes that hydrophobic matching between lipid-bilayer hydrophobic thickness and hydrophobic length of the integral protein is an important aspect of the interactions. By means of Monte Carlo simulation techniques, the lateral distribution of the two lipid species near the hydrophobic protein-lipid interface in the fluid phase of the bilayer has been derived. The results indicate that there is a very structured and heterogeneous distribution of the two lipid species near the protein and that the protein-lipid interface is enriched in one of the lipid species. Out of equilibrium, the concentration profiles of the two lipid species away from the protein interface are found to develop a long-range oscillatory behavior. Such dynamic membrane heterogeneity may be of relevance for determining the physical factors involved in lipid specificity of protein function.

Mean-field and Monte Carlo simulation studies of the lateral distribution of proteins in membranes

Monte Carlo simulations and mean-field calculations have been applied to a statistical mechanical lattice model of lipid-protein interactions in membranes in order to investigate the phase equilibria as well as the state of aggregation of small integral membrane proteins in dipalmitoyl phosphatidylcholine bilayers. The model, which provides a detailed description of the pure lipid bilayer phase transition, incorporates hydrophobic matching between the lipid and protein hydrophobic thicknesses as a major contribution to the lipid-protein interactions. The model is analyzed in the regime of low protein concentration. It is found that a large mismatch between the lipid and protein hydrophobic thicknesses does not guarantee protein aggregation even though it strongly affects the phase behaviour. This result is consistent with experimental work (Lewis and Engelman 1983) considering the effect of lipid acyl-chain length on the planar organization of bacteriorhodopsin in fluid phospholipid bilayers. The model calculations predict that the lipid-mediated formation of protein aggregates in the membrane plane is mainly controlled by the strength of the direct lipid-protein hydrophobic attractive interaction but that direct protein-protein interactions are needed to induce substantial aggregation.

Theory of protein-induced lateral phase separation in lipid membranes

An account is given of the current status of theoretical modeling of the phase equilibria in lipid membranes with intrinsic proteins. Special attention is paid to the description of lateral phase separation, which is important for membrane function since it may lead to biologically differentiated regions. We discuss in particular the mattressmodel approach by Mouritsen and Bloom (37), who take matching between protein and lipid hydrophobic thicknesses as a determining factor for the phase behavior. The model has been developed in the framework of phenomenological thermodynamics solution theory. The predictions of the theory are compared to a variety of experimental measurements, including those of membrane recombinants of the protein content of the reaction center and antenna protein of the bacterial photosynthetic apparatus as well as the erythrocyte band 3 protein. The physical effects of lipid-protein interactions are contrasted to those of lipid-cholesterol interactions. The concept of hydrophobic matching is then used as a basis for discussing a possible relationship between membrane thickness and physiological function.

Theory of phase equilibria and critical mixing points in binary lipid bilayers

The fundamental problem of determining the phase equilibria of binary mixtures is discussed in the context of two‐component phospholipid bilayer membranes of saturated phospholipids with different acyl‐chain lengths. Results are presented from mean‐field calculations and Monte Carlo simulations on a statistical mechanical model in which the interaction between lipid acyl chains of different length is formulated in terms of a hydrophobic mismatch. The model permits a series of binary phase diagrams to be determined in terms of a single ‘‘universal’’ interaction parameter. The part of the free energy necessary to derive phase equilibria is determined from the simulations using distribution functions and histogram techniques, and the nature of the phase equilibria is determined by a finite‐size scaling analysis which also permits the interfacial tension to be derived. Results are also presented for the enthalpy and the compositional fluctuations. It is shown, in accordance with experiments, that the nonideal...

Tools and data services registry: a community effort to document bioinformatics resources

Life sciences are yielding huge data sets that underpin scientific discoveries fundamental to improvement in human health, agriculture and the environment. In support of these discoveries, a plethora of databases and tools are deployed, in technically complex and diverse implementations, across a spectrum of scientific disciplines. The corpus of documentation of these resources is fragmented across the Web, with much redundancy, and has lacked a common standard of information. The outcome is that scientists must often struggle to find, understand, compare and use the best resources for the task at hand. Here we present a community-driven curation effort, supported by ELIXIR—the European infrastructure for biological information—that aspires to a comprehensive and consistent registry of information about bioinformatics resources. The sustainable upkeep of this Tools and Data Services Registry is assured by a curation effort driven by and tailored to local needs, and shared amongst a network of engaged partners. As of November 2015, the registry includes 1785 resources, with depositions from 126 individual registrations including 52 institutional providers and 74 individuals. With community support, the registry can become a standard for dissemination of information about bioinformatics resources: we welcome everyone to join us in this common endeavour. The registry is freely available at https://bio.tools.

Flip-Flop of Steroids in Phospholipid Bilayers: Effects of the Chemical Structure on Transbilayer Diffusion

The transverse motion of molecules from one leaflet to the other of a lipid bilayer, or flip-flop, represents a putative mechanism for their transmembrane transport and may contribute to the asymmetric distribution of components in biomembranes. However, a clear understanding of this process is still missing. The scarce knowledge derives from the difficulty of experimental determination. Because of its slow rate on the molecular time scale, flip-flop is challenging also for computational techniques. Here, we report a study of the passive transbilayer diffusion of steroids, based on a kinetic model derived from the analysis of their free energy surface, as a function of their position and orientation in the bilayer. An implicit membrane description is used, where the anisotropy and the nonuniformity of the bilayer environment are taken into account in terms of the gradients of density, dielectric permittivity, acyl chain order parameters, and lateral pressure. The flip-flop rates are determined by solving the Master Equation that governs the time evolution of the system, with transition rates between free energy minima evaluated according to the Kramers theory. Considering various steroids (cholesterol, lanosterol, ketosterone, 5-cholestene, 25-hydroxycholesterol, and testosterone), we can discuss how differences in molecular shape and polarity affect the pathway and the rate of flip-flop in a liquid crystalline 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) bilayer, at low steroid concentration. We predict time scales ranging from microseconds to milliseconds, strongly affected by the presence of polar substituents and by their position in the molecular skeleton.

A microscopic model for lipid/protein bilayers with critical mixing

A statistical mechanical lattice model is proposed to describe the phase diagram of phospholipid bilayers with small transmembrane proteins or polypeptides. The model is based on the extended Pink-Green-Chapman model (Zhang et al. (1992) Phys. Rev. A 45, 7560-7567) for pure lipid bilayers which undergo a first-order gel-fluid phase transition. The interaction between the lipid bilayer and the protein or polypeptide is modelled using the concept of hydrophobic matching. The phase diagram has been derived by computer-simulation techniques which fully account for thermal density fluctuations and which operate on the level of the free-energy thereby permitting an accurate identification of the phase boundaries. The calculations predict a closed loop of gel-fluid coexistence with a lower critical mixing point. Specific-heat traces across the phase diagram are also presented. The theoretical results for the phase diagram, the specific-heat function, and the transition enthalpy are related to recent experimental measurements on phospholipid bilayers mixed with synthetic transmembrane amphiphilic polypeptides or with gramicidin A.