Polymer physics in cellular organization and function
Location: CECAM-ES
Organisers
Polymer physics has proven a powerful, fruitufl and insightful branch of statistical physics, which has allowed to unify, classify and systematize the general properties of polymers when their local, detailed chemical composition does not play a central role.
Cellular functions are diverse and they take place in a crowded, complex medium that involves a large number of different organelles and biopolymers. As quantitative biological and physicochemical techniques advance we dispose of more precise measurements on the structure and function of cellular constituents, which help us to unravel the relevance of biopolymers in cellular function and metabolism. The potential of generic concepts coming from polymer physics, and their ability to unify, classify and systematize the properties and behavior of biopolymers, when it is in the complex and active environment that exists in a biological cell, is then a challenge at hand[1].
Among the many instances in which biopolymers contribute to cellular function, we have identified three paradigmatic cases where they are known to play a distinctive, non-trivial, central role: 1) Chromatin organization: the large scale structure of DNA, organized in the chromatin, and how it dynamically organises inside the cellular nucleus, is subject of intense research. Recent activities build on previous insight gained on the molecular strutcure of DNA at smaller scales to tackle the multiscale nature of DNA morphology, the larger scale strutcure and its sensistivity to the interaction with a confining medium and chemical activity; 2) biomolecular condensates have gained attention in past years and it is now accepted their role in a large number of cellular functions. In many cases these finite condensates are composed by a biopolymer mixture, in many instances undergoing chemical reactions (hence out of equilibrium). The role of polymer physics concepts to understand and clarify the mechanisms by which they phase separate, as well as their rmechanical properties, is a subject of vivid research; 3) Amyloid condensation: The selforganization of proteins in polymeric structures is of central importance in biophysics. Among the different type of protein aggregation, there exists a solid body of knowledge on amyloid fibril formation because of its implications in a number of diseases. Hence, understanding the general principles associated to fibril formation, condensation and cystalization has broader consequences in our generic understanding of the role of proteins and protein structures inside cells.
More specifically:
Chromatin Organization: The availability of experimental data on contact maps, 3D distances, phase separated nuclear condensates and TAD organization of chromatin have given us key insights into the three dimensional structure of chromatin [2]. While these organizing structures have key implications for transcriptional regulation, they have been revealed to be heterogeneous across cells [3] and dynamic and short lived in time [4]. These discoveries have led to two sets of theoretical studies using concepts from polymer physics. One set examined the nature of intra-chromosomal interactions that can generate experimentally observed contact probabilities and 3D distances [2]. The second set consists of nonequilibrium studies examining the role of loop extrusion, or the interplay between loop extrusion and intra-chromatin interactions resulting in the experimentally observed 3D organization, and chromosome as a semiflexible polymer with active stress fluctuations [5]. Recently there have been a few models examining the kinetics of histone modifications and the spreading of histone modifications around a nucleation site coupled with polymer dynamics[6]. While considerable progress has been made in understanding the structure of chromatin and the suitability of polymer models ( active and passive) in describing the static and dynamic structure of chromatin, the field is still at the very early stages.
Biomolecular condensates and liquid/liquid phase separation: Recent studies have highlighted that inside living cells, phase separation processes can lead to formation of biomolecular condensates that allow cells to organize spatio-temporally their contents beyond what is achievable with just membrane-bound compartments[7]. Hence, biomolecular condensation processes are increasingly recognized as a fundamental mechanism that living cells use to organize and control biomolecules in time and space[8].
Some of the best-studied examples of functional aggregates include nuclear condensates such as nucleoli, which are the site of ribosome biogenesis, and cytoplasmic stress granules, which play a role in the cellular stress response. Biomolecular condensates have also been found to regulate gene expression and facilitate cellular signaling pathways. Condensates contribute to healthy cellular function. In fact, it is known that condensate dysfunction correlates with disease. In this context, disruptions in biomolecular condensate formation have been linked to neurodegeneration and multiple forms of cancer.
The phase separation of intrinsically-disordered proteins into biomolecular condensates has taken centre stage in cellular physiology. Biomolecular condensates appear in numerous locations in cells where they carry out many biochemical functions[9].They modulate enzymatic activity, modulate buffer protein concentration, reduce noise in gene expression, and regulate cell migration. The proper functioning of the proteins is intrinsically related to their ability to phase separate[10].
The mechanical properties of these aggregates are also critical to determine its biological function. Although many biomolecular condensates are fluid, they do not behave as simple liquids[11]. A slow transition from the fluid phase to a rigid, fibrillous phase has been observed in vivoband in vitro for IDPs. Chromatin also undergoes phase separation in vitro, and restructures mechanically depending on its viscoelastic properties[12]. It has been conjectured that reversible phase separation is indicative of cellular health while irreversible rigidification of biomolecular condensatess marks a cell’s transition into disease states.The mechanistic understanding of how the molecular architecture of intrinsically disordered proteins controls their structure and mechanical properties remains a challenge.
Amyloid condensation: Amyloid fibrils constitute an important class of filamentous structures that result from the assembly of monomeric proteins or peptides with a characteristic core structure rich in beta-sheets. The interpretation of macroscopic observables determined in experiments in terms of the fundamental microscopic mechanisms that determine the aggregation behavior constitutes a major challenge[13]. Bridging this gap from microscopic to macroscopic scales requires a proper understanding of the fundamental processes that control amyloid formation at all intermediate length and timescales. Hence, polymer physics concepts can contribute to address the relationship between the scales and the nature and specificity of amyloid aggregation and structure formation in proteic solutions.
These three topics bring in a number of shared conceptual and computational challenges. Bringing together specialists in these systems will allow to explore the general underlying principles and mechanisms and how to benefit from our understanding of polymer physics in cellular biophysics[14]. Since in many cases these systems are out of equilibrium[15], we will also address how activity impacts the morphology and dynamcis of active/passive polymer mixtures subject to different types of activity[16], and also how activity impacts on their mechanical and rheological behavior[17].
References
Sunil Kumar P B (IIT, Madras) - Organiser
Spain
Beatriz Antoli (University of Zaragoza ) - Organiser
Ignacio Pagonabarraga (University of Barcelona) - Organiser & speaker