Competition between Phase Separation and Micellization in a Coarse-Grained Protein Model with Two Components

Abstract

Intrinsically disordered proteins (IDPs) are widely believed to play a key role in the for- mation of intracellular biomolecular condensates through liquid-liquid phase separation (LLPS). Furthermore, it has been shown in vitro that several IDPs are able to phase sepa- rate on their own. Computational modeling offers unique opportunities to investigate the driving forces and sequence-dependence of IDP LLPS. Prior computational studies have mainly focused on one-component systems. In this thesis, using a coarse-grained model, we investigate the aggregation behavior of systems composed of two hydrophobic/polar sequences, called A and B. On their own, sequence A forms droplets of a dense bulk phase, whereas sequence B forms micellar aggregates. Using Monte Carlo simulations, we in- vestigate the competition between these two aggregation mechanisms in mixed systems containing both sequences. Keeping the total number of chains fixed, we monitor the transition from sequence A-dominated droplet formation to sequence B-dominated micel- lization as the fraction of sequence B chains is increased. The transition entails major changes in both internal organization and size of the observed aggregates, and we find that a variety of intermediate species exist.

Popular Abstract

The interior of cells, the basic structural and functional unit of living things, contains various subunits called organelles. Classical organelles, such as chloroplasts and mitochon- dria, are separated from their surroundings by a membrane. Recent experimental advances have shown that, in addition, there exist organelles that lack a surrounding membrane and rather behave as liquid droplets, as was first demonstrated about a decade ago. These membraneless bodies harbour high concentrations of proteins and nucleic acids, and serve as an important complement to classical organelles in the internal organization of cells. Their formation amounts to a phase separation, with the droplet and its background rep- resenting two distinct liquid phases, like a droplet of oil in water. Over the past decade, the character and function of membraneless organelles have become subjects of intense interest.

Currently, it is widely believed that intrinsically disordered proteins (IDPs) play an im- portant role in biomolecular phase separation. Despite their lack of a well-defined 3D structure, IDPs are able to perform a variety of biological functions. Moreover, they fre- quently occur in membraneless organelles, and several such IDPs have been shown capable of generating droplets on their own. However, the ability of IDPs to phase separate has been shown to depend not only on their amino acid composition but also on the ordering of the amino acids along the protein sequence. Understanding this sequence-dependence is an important, largely unsolved problem. Some of the so far most extensively studied IDPs are linked to neurodegenerative diseases. The misfolding and aggregation of these IDPs may have a causative role in diseases such as Alzheimer’s and Parkinson’s. A potential phase separation could influence the aggregation properties of these disease-linked IDPs.

Exploring the mechanisms of biomolecular phase separation in realistic cellular environ- ments is a challenge. To be able to investigate the basics of biomolecular phase separation, many experimental and computational studies have therefore focused on idealized systems with a single component, typically an IDP. Such studies have, in particular, provided in- sight into how the ability to phase separate depends on the amino acid sequence. However, droplets inside cells are more complicated, as they contain several different proteins as well as nucleic acids. In this thesis, we explore the phase behavior of a two-component system composed of two IDPs, using a simple coarse-grained model. By computer simulations for a fixed total number of molecules, we in particular investigate how the behavior of this system varies with the relative amount of the two components. We show that both the size and character of the clusters formed in these systems depend strongly on the relative amount of the two sequences.

• author: Lyu, Fangxuan
• supervisor: Anders Irbäck
• organization: Department of Astronomy and Theoretical Physics - Has been reorganised; Computational Biology and Biological Physics - Has been reorganised
• course: FYTM03 20212
• year: 2022
• type: H2 - Master's Degree (Two Years)
• subject: Physics and Astronomy
• language: English
• id: 9074872
• date added to LUP: 2022-03-01 11:40:36
• date last changed: 2022-06-28 11:23:10