They are also highly abundant, composing a large fraction of the eukaryotic proteome ( 11). IDPs are proteins that do not adopt a stable folded structure, yet are able to carry out biological functions ( 11). Recent studies have linked protein intrinsic disorder to MLOs, showing that the proteome for MLOs has a significantly greater fraction of proteins containing intrinsically disordered regions ( IDRs) than the overall proteome ( 10). 2. STRUCTURE VERSUS DISORDER 2.1. Role of Intrinsic Disorder in Phase Separation We therefore place particular emphasis on the role that simulation can play in exploring the space of sequence, structure, and phase properties of intrinsically disordered proteins ( IDPs). In addition, simulations allow rapid screening of sequence changes or other modifications, which may be more costly to do experimentally. Molecular simulations can play an extremely valuable role in this situation, providing detailed information on the driving forces behind phase separation (which can of course subsequently be tested against experiment) they can also be used for developing and testing new analytical theories. Elucidating such interactions by experiment is challenging owing to the heterogeneous structure of components within MLOs, such that any observables are always averaged over a broad distribution of structures. In this review, we discuss the different types of biomolecules that participate in LLPS and the formation of MLOs, and we provide some perspective on what interactions contribute to phase separation, how these interactions may be altered by environmental conditions, and how overall interactions between components promote phase separation of multiple components into two or more phases. Gaining a greater understanding of the normal and pathological functions of MLOs requires a clear view of the molecular interactions underlying LLPS and of how different biomolecules may contribute to the process of phase separation. MLOs have also been linked to the formation of pathological aggregates associated with neurodegenerative diseases such as amyotrophic lateral sclerosis, frontotemporal dementia, and Alzheimer's disease ( 1, 7– 9). MLOs differ from membrane-bound organelles in their ability to spontaneously form and dissipate ( 2, 4) and their permeability ( 5, 6). These organelles, which lack a surrounding lipid membrane, have demonstrated liquid-like properties ( 2) and are characterized by a region of highly concentrated proteins and frequently also nucleic acids, coexisting with the surroundings through the process of liquid-liquid phase separation ( LLPS) ( 3). Membraneless organelles ( MLOs) have recently been shown to occur in a variety of biological contexts, facilitating a wide array of functions requiring compartmentalization ( 1). We finally discuss how these molecular driving forces alter multicomponent phase separation and selectivity. In this review, we discuss the role that disorder, perturbations to molecular interactions resulting from sequence, posttranslational modifications, and various regulatory stimuli play on protein LLPS, with a particular focus on insights that may be obtained from simulation and theory. Elucidating the molecular determinants of phase separation is a critical challenge for the field, as we are still at the early stages of understanding how cells may promote and regulate functions that are driven by LLPS. These droplets are termed membraneless organelles, as they lack a dividing lipid membrane, and are formed through liquid-liquid phase separation (LLPS). Biological phase separation is known to be important for cellular organization, which has recently been extended to a new class of biomolecules that form liquid-like droplets coexisting with the surrounding cellular or extracellular environment.
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