Lipid membranes and proteins, which are part of us throughout our lives, have been studied for decades. However, every year, new discoveries show how little we know about them. In a reader-friendly manner for people not involved in the field, this paper tries to serve as a bridge between physicists and biologists and new young researchers diving into the field to show its relevance, pointing out just some of the plethora of lines of research yet to be unraveled. It illustrates how new ways, from experimental to theoretical approaches, are needed in order to understand the structures and interactions that take place in a single lipid, protein, or multicomponent system, as we are still only scratching the surface.

Cells are the basic units of the human body and are composed of essential components for their proper functioning, such as cytoplasm, membranes, and organelles. Among these, lipid membranes stand out, as they are synonymous with the existence of life.1,2 Membranes consist of a surrounding lipid bilayer that ensures their integrity, with two layers of parallel lipids arranged tail-to-tail. This barrier is formed by the self-assembly of amphiphilic compounds, such as simple fatty acids, which are characterized by a polar or hydrophilic head and a nonpolar or hydrophobic tail.3 The major membrane lipids are classified into glycerophospholipids (GPLs), sphingolipids (SLs), and sterols (mainly cholesterol),4 and a plethora of modifications can be found in each of their moieties, resulting in a broad lipid library of more than 1000 lipid types. They can be described by (un)saturated fatty acids of different lengths, fatty acid linkages, backbones, and/or head groups, among others.5 Altogether, they allow cells to store and regulate energy, to transmit signals and information, and to compartmentalize, as these ∼3–4.5 nm thick hydrophobic films can also be present in their internal compartments,6 with specific compositions depending on their crucial role.7 

However, they are not alone, as membrane proteins are also present. They constitute nearly one third of all human proteins and are essential determinants of membrane-bound processes. These proteins can be divided into integral membrane proteins (IMPs), which are embedded in the lipid bilayer, and peripheral membrane proteins (PMPs), which are anchored to the surface on one side of the membrane. IMPs have a unique structure characterized by the presence of lipid solvation around them,8 whereas PMPs are completely soluble in water and reversibly interact with one side of the bilayer.9 Moreover, external proteins present in the medium can also interact with the cell membrane. While some of these proteins have a fixed structure, it was not until recently that intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs) were discovered, adding another layer of complexity to the field.10 IDPs are described by proteins that do not show a concrete or stable tertiary structure, but are still functional. Similarly, IDRs are described when only a section of the protein lacks fixed conformation.11 Generally found in nature, IDRs are present in at least 2.0% of archaeal, 4.2% of eubacterial, and 33.0% of eukaryotic proteins.12 More specifically, in humans, it has been reported that 44% of protein-coding genes contain disordered segments of >30 amino acids in length.13 Thus, an infinite number of lipid-protein combinations can occur that can lead to several changes not only in the lipid, but also in the protein arrangement.

During the last few decades, several groups have focused their research on the elucidation of lipid and protein conformations, as well as lipid-protein interactions. However, the lateral structure and the specific recognition processes of the latest remain to be clarified. Lipids have been considered a passive layer that merely supports proteins, but only recently, they have attracted attention again and have been proposed as specialized binding molecules. Moreover, the structure-behavior relationship of several proteins is still a challenge in itself and requires a deeper understanding. This perspective article aims to show what general lines of research are currently open and what remains to be understood for newcomers to the field. Complemented by examples and several references that can help to dig more into the topic itself, it illustrates how important it is to understand the molecular interactions occurring in these living systems for their implementation in our daily lives. In summary, this work shows their complexity and the challenge that lies behind them.

To unravel the interactions that take place at the lipid-protein interface, it is necessary to know how both elements behave independently. In recent years, we have witnessed an increase in the amount of information, and publications, describing proteins and lipid membranes. While their composition begins to be known, the link between their molecular structure or sequence and their behavior is missing or only “suggested.” Here, a brief overview of the current state of the art is given, while for a more in-depth look, we recommend the referenced literature.

At present, after decades of meticulous study, we can boldly suggest that we have elucidated the basic functions of several lipids present in the human body when isolated. They can act as anhydrous reservoirs, segregate or compartmentalize regions by membrane formation, and/or participate in signal transduction and molecular recognition processes.14 However, their behavior as a group in complex environments, such as living systems, remains elusive. In cells, lipid membranes can adopt fluid and solid phases, as described by the spatial arrangement and freedom of movement that each lipid assumes with respect to its neighbors. Long saturated hydrocarbon chains favor solidlike phases, while unsaturated hydrocarbon chains, such as most biomembranes based on glycerophospholipids, lead to liquid phases. However, most of the model membranes currently proposed and studied are far from being real. Each membrane-based organelle has a characteristic composition, where lipids can also be asymmetrically distributed between the two leaflets.15 In model membranes, lipid exchange between layers is rather low compared to real systems, as the half-time of GSL translocation can be days instead of minutes or even seconds. Moreover, the addition of other lipids, sterols, can quickly induce affinity rotations or trapping.16 Even cholesterol, well known and abundant in several lipid membranes, has been reported to have a high affinity for SLs, but with a controversial orientation that remains to be clarified.17 Furthermore, other specific and dynamic processes are present in lipid membranes. Selective lipid transport exists in living systems, as not every lipid is synthesized in the organelle where it is ultimately present. The plasma membrane, lysosomes, and endosomes rely on lipid transport.3 This process is directly related to the asymmetry of the membranes and the formation of nano- or microdomains. These small-size and highly dynamic regions can also be formed in lipid membranes for short periods of time, promoting liquid-solid transitions and ultimately alternative membrane interactions or behavior.18,19 They are characterized by different physical phase states, chemical composition, and properties depending on the lipid composition. For example, ceramides can induce rigidity, highly condensed monolayers, and self-aggregation.20 GSLs have bulky headgroups that lead to conformational constraints and sugar-water interactions,5 and phosphoinositides promote membrane interactions of divalent cations, cholesterol, specific binding proteins, or charged systems.21 However, how the interleaflet coupling or how both sides of the membrane communicate with each other and how their modification is originated are yet to be understood. Recent works propose molecular/protein pinning as key aspect in interleaflet communication, promoted by nanodomain formation, while a new set of more complex experiments are needed.22 In addition, we must consider the membrane curvature,23 such as protrusions or invaginations, which are directly related to specific biological interactions, local membrane composition, transbilayer coupling, and membrane fluidity. Lipids have specific shapes, such as the well-known conical one, or a modulated one, such as cardiolipin. Thus, the lipid composition is directly related to its final structure and behavior. At present, most of the works in this line are centered in vesicles with a natural curved shape.24 However, the presence of nanodomains in these systems could not be enough and more extended or large-scale models should be designed and studied. Finally, their interactions with some salts, known as room temperature ionic liquids (ILs), are also being studied in pharmacology, drug delivery, biomedicine, and bionanotechnology, with much room for development.25 For a complete review of membrane lipids, we recommend the work of Cebecauer et al.22 In summary, a deep understanding of biological membranes is necessary. New model membrane systems need to be developed to incorporate the asymmetry and dynamic changes mentioned above. Works, such as Ayscough et al., where a perfectly functional not constrained bilayer is placed beneath a monolayer at the air-water interface to study transmembrane proteins, are more than needed.26 

Traditionally, proteins have been viewed as long, folded peptide chains with a well-defined secondary, tertiary, or quaternary structure that determines their ultimate properties and function, following a “lock and key” model.27 If any structural change was observed in a protein, it was due to an alteration in its sequence or medium. While it is true that some proteins require a specific structure to function properly, for others, such as IDPs or IDRs, their structure can be “flexible” and change in situ according to the desired application. Rather than acting as mere connectors, they behave as building blocks that add value to the final structure. Proteins with a fixed structure have started to be classified in function of their sequence-assembly-functionality (e.g., Pfam or Superfamily databases),28,29 while its implementation is still necessary for disordered structures. Some authors have already tried to associate specific regions and amino acid sequences with their functionalities, such as molecular recognition, protein modification, molecular assembly, or entropic chains.30 They have also distinguished them by their permanent, transient, or nonbinding interactions.31 For a broad overview of the classification of IDPs and IDRs, we recommend the work of van der Lee et al.13 Nevertheless, this classification is far from being even preliminary. Several proteins are still beginning to be unraveled as IDPs or to have IDRs, and even less is known about their dynamic structure-behavior relationship. As of now, researchers started to associate amino acids with final assembly properties. They have divided them into order-promoting residues (Asn, Cys, Ile, Leu, Phe, Trp, Tyr, and Val) or enriched in disorder-promoting residues (Ala, Arg, Gln, Glu, Gly, Lys, Pro, and Ser).32 Also, they have been able to link the unstructured behavior to the presence of tandem repeat units.33 However, their sequence and medium are also key factors to consider. A low content of hydrophobic amino acid residues along with large net charges and pI values are proposed to lead to IDRs due to their low energy advantage in assuming a compact assembly.34 IDPs, such as α-synuclein, αs-casein, or the phosphodiesterase γ-subunit, self-assemble into a more ordered structure at higher temperatures due to the enhancement of hydrophobic interactions.35–37 Others, such as human peptide LL-37 or prothymosin α, increase their fixed structural propensity when the net charge is neutralized, as intramolecular charge/charge repulsions are removed.38,39 Transitions from random coil to ordered, going through molten globule or premolten globule conformations, have been predicted and reported in these systems.40,41 Based on these findings, a case-by-case study is most often required. We need to understand each protein. For instance, when interacting with other systems and despite their lack of stable structure, IDPs and IDRs can adapt to a variety of biological systems. They can use binding sites or receptors that lead to the formation of complexes with other proteins, where disorder-to-order transitions are often observed.42 Furthermore, it has recently been reported that, in some cases, they also retain a long-range flexibility and a highly dynamic character.43 For a comprehensive view of the assembly of IDPs and IDRs, we recommend the work of Uversky.32 Finally, phase separation systems are also directly related to them. Basic cellular processes often require a sequential cascade of reactions in specific environments or discrete subcellular compartments. Proteins and/or RNAs can segregate from them in the cytoplasm, leading to nonmembrane compartments or membraneless organelles (MLOs).44 These cell components are stable complexes defined by multivalent weak interactions between biological polymers at the nano- or micron-scale.45 In recent years, reports on MLOs and their direct relationship to diseases, such as cancer, frontotemporal lobar degeneration (FTD), or amyotrophic lateral sclerosis (ALS), have demonstrated their relevance in the study of disease pathology and treatment.46 However, despite some breakthroughs, our understanding of them is limited. The more questions we answer, the more they arise. Why do they show specific changes in structure and interactions? What are the key recognition amino acids that lead to the perfect behavior of the protein? Alternatively, what can or should not be changed for the proper functionalization of a protein? These are just some of the questions that remain to be answered.

As if all the previously mentioned was not enough, lipids and proteins appear together in a symbiosis most of the time in the study and understanding of biological systems, drastically changing their behavior. In this line, their interactions could be divided based on the protein fixation or anchor to the lipid membrane. Thus, we can categorize them as integral membrane proteins (IMPs), monotopic membrane proteins (MMPs), and peripheral membrane proteins (PMPs).

These membrane-spanning proteins, responsible for the metabolite transport and communication, represent ∼25% of the protein-coding genes in all organisms47 and can be found in the lipid membrane or inserted directly into the plasma membrane.48 After being synthesized in the ribosome, IMPs target, insert, fold, and assemble at the membrane, resulting in either a single-pass (bitopic) or multipass (polytopic) membrane, as shown in Fig. 1(a) (left). With more than 5000 different IMPs in the human body alone, their biogenesis and final assembly at the lipid membrane is still the focus of research. The preliminary theory, based on a unique and determined protocol in which their hydrophobic moieties dictated their binding and final interactions, has been exchanged by several routes wherein the sequence of the polypeptide dictates the final pathway.49 The protein can target the membrane via the signal recognition particle (SRP) targeting pathway, the insertion pathway mediated by the ER membrane protein complex (EMC), and the guided entry of the tail-anchored protein (GET) insertion pathway. Upon arrival, its transmembrane domains (TMDs) are inserted in an unassisted, insertase-mediated, or channel-mediated pathway and eventually fold and assemble, ready to function. However, the key lipid-protein or protein-protein factors and steps that occur during this complex process remain poorly understood, studied, and sometimes even overlooked. For instance, there is no clear mechanistic information regarding the yeast SRP-independent (SND) targeting pathway or the recent role of Nexo signaling anchors of type III proteins in the ER membrane protein complex (EMC).50 Furthermore, newly proposed targeting pathways require further research, as only the SRP pathway is fairly elucidated,51 compared to the SND or GET pathways.52 The assembly of proteins also needs to be further developed, as a random diffusion model, although plausible, is rather unlikely and too arbitrary.50 Work, such as that of Zaborowska et al., where for the first time the membrane protein HMG-CoA reductase, responsible for cholesterol synthesis, was incorporated into a lipid membrane consisting of DOPC:Chol:SM at a 1:1:1 molar ratio, may pave the way.53 

FIG. 1.

(a) Classification of membrane proteins in function of their assembly and anchoring to the lipid membrane. (b) Representative membraneless condensate formed by phase separation of a protein. Created by the author with BioRender.com.

FIG. 1.

(a) Classification of membrane proteins in function of their assembly and anchoring to the lipid membrane. (b) Representative membraneless condensate formed by phase separation of a protein. Created by the author with BioRender.com.

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This group of proteins is described as being embedded on only one side of the lipid membrane and often appears to be associated with catalyzing reactions on membrane-resident substrates. Depending on their active site, these enzymes can simply “extract” hydrophobic substrates from the lipid bilayer for catalysis or “move” to the lipid instead.54 While already this broad topic based on dynamics is another area that requires further development, these proteins are known to interact with the membrane by functional dimers, amphipathic helices, long hydrophobic loops, hydrophobic patches surrounded by positive charges, re-entrant membrane helices, or just by the linker and the protein being an isoform of each other.55 However, many proteins follow a unique interaction, perhaps forming new folds not observed in soluble homologs.56,57 Proteins, such as LpxM from E. coli, have an unknown attachment, as a re-entrant helix process has only recently been proposed.58 More importantly, their structure, while determined in some cases, lacks a critical point: the membrane-binding domain. Although this is a step forward, their protein structure is not properly understood due to the study of their truncated version, where the importance and effect of the binding region are neglected. New approaches are needed to characterize these protein-membrane interactions to map what is really happening. We only know one point in a complete picture, which may not be very accurate.

PMPs, such as phospholipases and lipases, are characterized by their water solubility and reversible interactions with membranes at the lipid-water interface, as shown in Fig. 1(a) (right). Their binding can be achieved by electrostatic or hydrophobic interactions, structural domains, or by a cascade of binding events facilitated by other proteins. As previously mentioned before, the structure of the lipids, their charge, the ions present, the polarity, and the geometry of the protein are just some of the parameters to consider in understanding these interactions.59 Membrane contact sites (MCSs) can also be promoted by nanodomains in response to concentration gradients or charge changes on the membrane surface, although their formation, regulation, and specific interactions remain elusive.60 For instance, these proteins can act as lipid transporters for sterols, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidylserine (PS) with an unknown mechanism.61 Their properties make them unique in the development of cures for diseases, such as tuberculosis, cancer, or parasitic infections.62 However, their dynamic behavior poses a challenge. Most work has focused on proteins alone, where lipids are absent, and those that have used them are just simple lipid barriers, far from the real biological environment. Novel planar bilayer techniques are being developed, with much room for improvement.63 For instance, drugs that have been found to actively influence PMPs in solution have been also reported to have a completely different behavior when present in a membrane.64 Thus, knowing the differences between their behavior in the presence of lipids, proteins, or both together is a real gray area of research that needs to be unraveled.65 

In the absence of lipids, proteins were recently reported to phase separate or compartmentalize on their own with the discovery of P granules in 2009.66 A hot topic of research that goes back and forth, phase separation plays a key role in several cellular processes, such as the formation of MLOs, signaling complexes, the cytoskeleton, and numerous other supramolecular assemblies, as shown in Fig. 1(b).67 Commonly known as liquid-liquid phase separation, even their designation is controversial, as they can behave as liquids, but also as solids, liquid–gels, solid–gels, crystalline–solids, semicrystalline–solids, or liquid–crystals, depending on the protein assembly.68 For instance, heterochromatin was considered to be highly pack and stable, while new reports propose more dynamic behavior.69 An increasing number of structured proteins, IDPs, or proteins with IDRs are reported to exhibit this behavior, modulated by factors, such as protein or salt concentration, pH, or other molecular crowders, such as polyethylene glycol (PEG) or RNA.70,71 Multivalency has been proposed as a key factor in driving phase separation, as it exhibits higher affinity, high stereospecificity, and allows the assembly into large oligomers or polymers.72 However, this biological phenomenon also remains poorly understood. While several papers have been able to assemble some of these condensates in vitro for their study,73 the dynamic nature of their formation, function, and physiopathology has only emerged fairly recently. Their differences from canonical protein complexes, the essential amino acids or regions required for phase separation, their internal organization in living systems, structural changes, mutations, aging, relationship to diseases, or their liquid-to-solid effect are just some of the multiple questions still pending to be answered. Finally, their behavior in more complex systems, such as fibrillar networks, is also under development, where new models are proposed.74 

To address all these challenges, physicists and biologists alike have tried to elucidate their structures from two complementary perspectives: experimental and theoretical. Fortunately for us, most of these techniques can be applied to lipids, proteins, and lipid-protein assemblies, although their implementation is not easy. While an entire book could be written on this subject, this perspective work will only mention most of the well-known techniques used, hoping to open new avenues of study and ideas for the reader in the development of this vast field. Our apologies for the omission of several important works in the field.

These biointerfaces have been explored in both 2D and 3D systems.75 Planar interfaces, such as the air/water interface, have been used to mimic several living media, such as lung surfactants or tear films,76 or to model hydrophobic biological environments.77 They can also be employed to study proteins per se at interfaces, as their aggregation under these conditions can lead to dysfunction of physiological processes.78 In addition, they can be applied to study lipid-protein systems, ranging from a simple peptide-POPG monolayer,79 to more complex lipid-multiprotein systems. Langmuir monolayers are extremely valuable models for membranes, providing valuable insights while overcoming the limitations of invasive methods.80,81 A model lipid barrier can be spread on an aqueous surface, and its behavior can be observed under defined conditions and/or in contact with specific molecules or drugs. Thus, changes in the lipid composition can be studied. Compression isotherms,82 ellipsometry,83 infrared reflection absorption spectroscopy,84 UV–visible reflection–absorption spectroscopy,85 Brewster angle microscopy,86 fluorescence microscopy,87 synchrotron-based x-ray methods,88 or sum frequency generation microscopy,89 or even cryo-EM90 are just some of the techniques used to characterize them, as shown in Figs. 2(a) and 2(b). The monolayers can also be transferred to solid substrates and further characterized. Langmuir–Blodgett (LB) or Langmuir–Schafer (LS) films, as shown in Fig. 2(c), can be analyzed in a complementary manner, e.g., by Atomic Force Microscopy (AFM) or attenuated total reflectance-FTIR,91,92 as their transfer to the substrate can retrain the monolayer properties, for instance, in LS films of bovine erythrocyte membranes.93 Alternatively, a profile analysis tensiometer (PAT), more precisely a coaxial double capillary PAT (CDC-PAT), could also be employed. In short, by exchanging solutions, it is possible to deposit specific lipid monolayers covering the droplet formed at the air-water interface and to analyze its surface tension when interacting with other polymers, as has already been done for DMPG, along with poly(styrene sulfonate) sodium salt (PSS) and poly(allylamine hydrochloride) (PAH),94 and possibly proteins.

FIG. 2.

Schematic of (a) Sum frequency generation. (b) Brewster angle microscopy. (c) Langmuir–Blodgett film deposition. Created by the author with BioRender.com.

FIG. 2.

Schematic of (a) Sum frequency generation. (b) Brewster angle microscopy. (c) Langmuir–Blodgett film deposition. Created by the author with BioRender.com.

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Complementarily, these studies can also be extrapolated to 3D systems or bulk, where lipids can be assembled in the form of micelles or vesicles,95 and proteins will be present under biological conditions.10 The same could be said for the final lipid-protein complexes. A fundamental description of underlying the kinetic and thermodynamic variables can be obtained. Calorimetry,96 nuclear magnetic resonance,97 circular dichroism,97 electron paramagnetic resonance,98 Raman spectroscopy,99 infrared spectroscopy,100 small angle x-ray scattering,101 or static and dynamic light scattering102 are just some of the platforms used to understand protein behavior, while most of them are yet to be properly characterized. Although more difficult to characterize, the final 3D self-assembled structures would be closer to the real medium in cells, where techniques, such as those cited above for proteins themselves, can be applied. For instance, a recent work comparing vesicles with monolayers using ellipsometry, x-ray scattering, and x-ray fluorescence has shown that both systems have significantly different structural features while having identical molecular composition,103 which could lead to different interactions and final conclusions.

Molecular modeling allows comprehensive exploration of the dynamic behavior of membrane proteins, which is sometimes difficult to assess with experimental techniques. However, when approaching these systems, the first step is to target the scale of the system and the interactions that need to be understood in order to choose the model. For lipids, proteins, and lipid-protein interactions, most simulations will use an atomistic model, where each atom is explicitly described, or a coarse-grained (CG) model, where regions of molecules are averaged in one bead while behaving similarly to the entire group.104 By sacrificing molecular detail and degrees of freedom, the CG model will, on average, allow longer simulation times in less time with the same computing power. Some studies even combine the two, detailing only the region of the protein they are really interested in Ref. 105. Nevertheless, more and more work is beginning to point out that CG is the way to go, as biological processes involve large protein assemblies and/or long timescale dynamics. CG models include two components: mapping from atomistic structures to coarse-grained (CG) “beads” and a set of potentials describing the interactions between the beads.106 Several mapping models have been proposed, such as AWSEM,107 OPEP,108 PLUM,109 SIRAH,110 SPICA,111 UNRES,112 or the famous Martini.113 For a detailed summary of these force fields, the work of Borges-Araújo et al. is highly recommended.114 In the case of proteins, each residue can range from 1 to 6 beads, and for lipids, such as dipalmitoylphosphatidylcholine or DPPC, it goes from 130 atoms down to 12 beads or even 3, as shown in Fig. 3. However, they clearly show some strengths but also weaknesses. Most of their calibration and validation follows a top-down approach and relies on reproducing experimental data (density, heat of vaporization, and partitioning), or a bottom-up strategy where CG interactions are extracted from atomistic results or structural databases. Thus, only for IDPs and IDRs, new and updated atomistic force fields are published every year trying to predict their self-assembly,10 while for CG models, the accuracy of the model seems to depend on the level of detail applied specifically to the backbone region and the final flexibility of the protein.

FIG. 3.

Schematic of a DPPC molecule going from atomistic (left) to Martini (4-to-1 mapping, center) and Cooke representation (right). Created by the author with BioRender.com.

FIG. 3.

Schematic of a DPPC molecule going from atomistic (left) to Martini (4-to-1 mapping, center) and Cooke representation (right). Created by the author with BioRender.com.

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Not everything is negative, however. Multicomponent membranes in which lipid domains, bilayer asymmetry, binding of specific lipids to membrane proteins, membrane-mediated protein−protein interactions, and lipid- or protein-induced membrane undulation effects are developed. Accurate lipid-based systems have been achieved by this approach, with a large library of sugars, membranes, or even small drugs already in the Martini force field. The new atomistic and CG models, instead of pushing in parallel, begin to fuse and implement their strengths, leading to realistic cell membranes, as widely detailed by Marrink et al.115 For instance, complex plasma,116 organelle,117 bacterial,118 or skin membranes119 have been proposed in recent years. Furthermore, researchers are going one step further and started to simulate large-scale complex dynamic events in the cell, where supra-CG models show large-scale membrane organization or membrane remodeling. Finally, a note on the emerging field of machine learning (ML).120 As these models are not at the level of their atomistic counterparts, ML CG models could be the future for their design in a bottom-up approach. Automatic parameterization strategies, mainly using artificial intelligence (AI) strategies, will influence new CG models in the near future, as Martini is trying to do in protein folding and binding,121 or other neural networks too.122 

With all these missing studies and understandings in mind, new enigmas have emerged in recent years, leading to several hot topics of research. Here, we list some of the most prominent open questions and future fields where this knowledge can be applied:

Dissipative self-assembly (DSA) is crucial for understanding how living systems create and maintain their highly organized states far from thermodynamic equilibrium. Living organisms are based on the formation and maintenance of organized structures through continuous energy input and dissipation, using energy and fuel from the environment to perform their functions, such as self-healing, homeostasis, and camouflage.123 For instance, proteins can be used as building blocks for synthetic dissipative cross-linking of transient hydrogels controlled by their hierarchical structure,124 or artificial supramolecular dissipative systems can also be proposed. Based on the (de)phosphorylation of a peptide-based supramolecular assembly, it induces the formation of transient fibers that are maintained over time by a constant supply of fuel (i.e., ATP) and removal of waste.125 In the world of cell membranes, vesicles are also formed by DSA, as peptides can self-assemble into membranes, for example, with chemical reaction cycles driven by the energy gained from the hydrolysis of a carbodiimide.126 

The structure of condensates has long been characterized by their coupled associative and segregative phase transitions, or how they form or dissolve upon functional changes in the media or in the protein structure. Complex coacervation or polymerization-induced phase separation are just some of the processes studied. In intrinsically disordered domains, these interactions are not so clear, even for classical regions based on simple systems with sticker-and-spacer architectures.127 Furthermore, it has recently been found that their interfaces play an important role in condensate formation, and a more biophysical approach is required to understand their behavior since the thickness of the interface is larger than the average size of a macromolecule within the condensate.128 Their adsorption and wetting transitions, or viscoelastic properties, are just some of the parameters that should be taken into account to understand their interfacial free energies and specific behavior.129 

With the understanding of their formation, stability, and configuration, more and more researchers are trying to replicate and exploit the properties of condensates and organelles in the final formation of complex cells.130 As mentioned earlier, more and more researchers are comparing the behavior of amino acids and proteins with building blocks and polymers. Thus, several groups have developed them based on polysaccharides, polypeptides, and proteins, such as Elastin Like Polypeptides (ELPs), for the final formation of artificial reversible organellelike microcompartments,131 or the use of synthetic cell membranes based on the self-assembly of amphiphilic comb polymers into vesicles.132 Furthermore, these organization processes can be controlled by external factors, such as light.133 Others have proposed the use of DNA in building up programmable coacervates to elucidate their dynamics, fusion, phase transition mechanisms, and wetting behavior,134 but also their ultimate application in synthetic cells as minimalist life forms.135 A final cell will need to integrate biomimetic functions, such as energy supply, protein expression, or growth-driven metabolism.136 However, the recent work by Ronit Freeman and colleagues makes this idea feasible, as they have demonstrated the ability to program DNA in order to enable a reconfigurable cytoskeleton that can assemble at specific locations and dynamically modulate its structural and mechanical properties.137 

Membranes remain as the barrier that separates us from the understanding of biological processes. Even being studied since the early 1900s, lipids should remain as a hot molecule of research due to their protein-binding motifs. Their relevance in protein function is obvious as the number of lipid-protein interactions discovered every year is rising. At the same time, this could not only mean other thing that proteins themselves need to be understood. An extensive work is still needed to unravel their structural transitions and their sequence-activity-applicability relationship.138 With the preliminary knowledge of lipids and proteins by themselves, we will then be able to provide a proper view of their interactions. Moreover, their clarification is a must to further implement their binding and recognition properties in various fields, ranging from the development of suitable drugs and medicines, biosensors, and biomaterials, to a final complex synthetic system, such as cells.

For this purpose, novel methodologies and approaches to these unsolved problems need to be proposed. Focusing on molecular simulations, considering the progress made in recent years, and the coming use of AI, we could say that we have a roadmap to reach real model systems. However, we could be hitting a bottleneck point where the experimental data could stop this evolution. Thus, experimentally, new super-resolution methods must be developed, as well as systems of study closer to the real medium that we have in us, living beings. While never forgetting the relevance of simplified systems to understand the basic forces behind their behavior and interaction, we should evolve from our actual static systems to more applied dynamic ones and, although easy for nature, it is a challenge that remains to be faced.

This work was supported by the Max Planck Institute for Polymer Research (MPI-P). The author would like to acknowledge the von Humboldt Foundation. The Table of Content and the figures were created with BioRender.com.

The author has no conflicts to disclose.

Ethics approval is not required.

Pablo G. Argudo: Conceptualization (lead); Writing – original draft (lead); Writing – review & editing (lead).

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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