TABLE 1.

Comparison of the main membrane characteristics proposed by the Singer and Nicolson (1972) model and the current cell membrane vision (based on Engelman (2005), Bagatolli (2010), Goñi (2014), Nicolson (2014), and references there in).

Singer and Nicolson (1972)	Today (2019)
The membrane consists of a double layer of lipids (bilayer) in a lamellar liquid-crystalline phase. (A preliminary deviation of this concept was included in the original model: “It is therefore not excluded that some significant fraction of the phospholipid (perhaps as much as 30 percent) is physically in a different state from the rest of the lipid.”)	In certain membranes, other phases like liquid-ordered phases or non-lamellar phases as rhombohedral, tetragonal, inverted hexagonal and cubic phases fulfill physiologically important functions. These phenomena involve membrane phase changes that are possible because of the intrinsic deformability of the membrane. Examples of transient non-lamellar phases can be seen during membrane fusion where from two independent bilayers originates only one which involves the coalesce of two bilayers (Chernomordik and Zimmerberg, 1995; Tenchov et al., 2006) or during pore formation by proteins as Bax/colicin family proteins and actinoporins which involves the formation of non-lamellar (semi-toroidal or toroidal) lipidic structures (Gilbert et al., 2014; Gilbert, 2016).
The membrane is considered flat.	Membranes are usually curved, dynamically modulated by the geometry of both lipids and proteins, and require asymmetry between both hemilayers in order to support this membrane curvature (Mouritsen and Bloom, 1984; Epand et al., 1996; Zimmerberg and Gawrisch, 2006; Bagatolli, 2010).
The protein:lipid ratio is 1.5–4, and thus proteins play an important role in the membrane structure. However, lipids and proteins do not interact strongly. They are almost independent entities, without significant perturbation of the bilayer. (A preliminary deviation of this concept was proposed in the original model: “if it is proposed that, while the largest portion of the phospholipid is in bilayer form and not strongly coupled to proteins in the membrane a small fraction of the lipid is more tightly coupled to protein. With any membrane protein, the tightly coupled lipid might be specific; that is, the interaction might require that the phospholipid contain specific fatty acid chains or particular polar head groups. There is at present, however, no satisfactory direct evidence for such a distinctive lipid fraction”.)	The membrane is full of proteins, leaving no membrane fraction unaffected by their presence. Protein–protein interactions have functional important signaling implications. There are lipids in direct contact with the protein (boundary lipids) that provide a special lipid environment for the proteins. Some of these lipids have a fast exchange with bulk lipids (annular lipids), whereas others (non-annular lipids) are tightly bound to certain membrane proteins stabilizing their conformation and/or function.
Proteins interact with the bilayer in two different forms: as peripheral or extrinsic proteins (associated to the lipid bilayer polar headgroups) and as integral or intrinsic proteins (associated to the hydrophobic matrix).	There are also other proteins that are only part of the time docked to a membrane (membrane associated proteins). They are not involved in the microstructure of the membrane; however, they have important membrane functions and dynamics. For example, protein kinases C and annexins (Bazzi and Nelsestuen, 1996).
The membranes are fluid. Lipids and proteins have two of three different modes of motion: rotational around an axis perpendicular to the plane of the membrane, and freely translational along the plane of the membrane. Transbilayer diffusion is forbidden because of the energy barrier presented by the hydrophobic matrix to the polar groups of the lipids and proteins.	The high amount of transmembrane proteins plus peripheral proteins plus protein-protein interactions restricts dramatically the lateral diffusion of proteins. The membranes are seen as “more mosaic than fluid.”1 Membrane lipids can also undergo fast transbilayer diffusion (flip-flop movements), which can be a protein-helped event or a spontaneous event. Scrambling of lipids contributes to the dynamic transbilayer asymmetry of the membrane; or, contrary to this, to losing the asymmetric condition by triggering a signaling process (i.e., phosphatidylserine flip-flop from the inner to the outer hemilayer and apoptosis).
The two surfaces of membranes are not identical in composition, structure, and distribution of oligosaccharides. This asymmetry is based on the forbidden transbilayer diffusion.	Membranes are asymmetric. Lipids and proteins are different in each hemilayer, this being a condition that involves lipid transporters or spontaneous lipid movements (Quinn, 2002; Daleke, 2003; van Meer, 2011). Integral proteins are naturally asymmetrical in the membrane after their initial biosynthesis. Asymmetry is essential for cells and its disruption is associated with cell activation or pathological conditions.
The membrane is mainly homogeneous. The original model suggested that: “Such short-range order is probably mediated by specific protein (and perhaps protein-lipid) interactions leading to the formation of stoichiometrically defined aggregates within the membrane. However, in a mosaic membrane with a lipid matrix, the long-range distribution of such aggregates would be expected to be random over the entire surface of the membrane”.	The bilayer is full of uneven heterogeneous patches or domains enriched in certain lipids and proteins, which confer irregular thickness in the membrane. This is the result of certain preference of protein-lipid contacts, mismatch between the length of the hydrophobic transmembrane segments of the proteins and the length of the lipid acyl chains, protein–protein contacts, the anchoring of integral proteins to cytoskeletal proteins, the poor miscibility of certain lipids, etc. These domains have very important functional implications. Membrane rafts (Simons and Ikonen, 1997) are one type of membrane domains. They are small (10–200 nm), transient and dynamic (short life, ∼200 ms). These domains, which induce lateral order and heterogeneous organization of membranes, are a consequence of the immiscibility of certain lipids of biological membranes, leading to the coexistence of patches with different physical properties and lipid compositions. They also compartmentalize or segregate certain proteins making more efficient a variety of cellular processes. Rafts domains in eukaryotic cell membranes are liquid-ordered domains rich in cholesterol and sphingomyelin. In model membranes, a mixture of lipids that induce a segregation of liquid-ordered (lo) and liquid-disordered phases (ld) is used to study those domains. A lo phase is a phase with higher lateral mobility in the bilayer than in a gel phase but with the lipid acyl chains extended and ordered, whereas a ld phase is a fluid phase with the acyl chains of the lipids highly disordered and mobile (Simons and van Meer, 1988; Simons and Ikonen, 1997; Brown and London, 2000; London, 2005; Sonnino and Prinetti, 2013).
The membrane is an isolated system with no exchange of matter or energy with the environment.	All kind of signals occur in the membrane contacting with the extracellular and intracellular environment, for example molecules reaching and leaving the membrane in response to stimulus (Watson, 2015; Wen et al., 2018).

¹Nicolson (2014) said: “I have re-termed the model as the ‘Fluid—Mosaic Membrane Model’ to highlight the important role of mosaic, aggregate and domain structures in membranes and the restraints on lateral mobility of many if not most membrane protein components.”