SNIC SUPR
Liquid-liquid phase separation of unstructured proteins
Dnr:

SNIC 2019/3-419

Type:

SNIC Medium Compute

Principal Investigator:

Anders Irbäck

Affiliation:

Lunds universitet

Start Date:

2019-08-15

End Date:

2020-09-01

Primary Classification:

10603: Biophysics

Secondary Classification:

10399: Other Physics Topics

Tertiary Classification:

10402: Physical Chemistry

Allocation

Abstract

Advances over the past decade have shown that, in addition to classical membranebound organelles, various membraneless droplets of proteins and nucleic acids, with liquid-like properties, can be found within living cells [1]. These droplets form through liquid-liquid phase separation, and, in many cases, intrinsically disordered proteins (IDPs) have been found to play a key role. Furthermore, several of these IDPs have been demonstrated in vitro to phase separate on their own. The aim of this continuation project is to develop and apply computational methods for modeling liquid-liquid phase separation of IDPs, and how the process depends on the amino acid sequence and solution conditions. This challenging problem is tackled using three main approaches: 1) Statistical field theory. Here, the original polymer problem is rewritten so that it can be investigated by field-theory simulations, based on the complex Langevin equation. This recently proposed approach [2] offers a potentially very useful alternative to explicit-chain simulation. 2) Coarse-grained explicit-chain simulation. Here, the goal is to study the phase behavior in a direct fashion, through reversible simulations of systems with many chains, during the course of which droplets form and dissolve many times. 3) Atomistic explicit-chain simulation with an implicit solvent force field. Here, single-chain structural properties and chain-chain interactions are investigated through simulations with a small (handful) number of chains, to collect data that will be used in parameterizing the coarse-grained model. The computationally most demanding part is the atomistic simulations, which are carried out using our program package PROFASI [3]. References: [1] For a review, see Y. Shin and C.P. Brangwynne, Liquid phase condensation in cell physiology and disease, Science 357, 1253 (2017). [2] J. McCarty, K. T. Delaney, S. P. O. Danielsen, G. H. Fredrickson, and J.-E. Shea, Complete phase diagram for liquid-liquid phase separation of intrinsically disordered proteins, J. Phys. Chem. Lett. 10, 1644 (2019). [3] A. Irbäck and S. Mohanty. PROFASI: A Monte Carlo simulation package for protein folding and aggregation. J. Comput. Chem. 27, 1548 (2006).