蛋白质“液-液相分离”的理论和计算方法进展

蛋白质分子的“液-液相分离”是近几年生物物理学领域迅速发展起来的研究热点.蛋白质相分离在一系列生物学过程中发挥着重要的作用.蛋白质分子序列和构象的多样性和复杂性,给蛋白质分子的理论研究、计算机模拟和实验研究都带来了巨大的挑战.当前,多尺度理论模型和多分辨率计算方法被广泛地用于蛋白质分子的“液-液相分离”的研究中.本文将对蛋白质分子“液-液相分离”的理论基础和计算机模拟方法进行简要的综述,并对这些理论和方法未来的发展趋势进行了初步的探讨和展望.期望为进一步研究蛋白质“液-液相分离”的物理化学机制和过程提供理论基础和方法借鉴.

Theoretical and computational methods of protein liquid-liquid phase separation

Liquid-liquid phase separation(LLPS)of proteins is an emerging field in the research of biophysics.Many intrinsically disordered proteins(IDPs)are known to have the ability to assemble via LLPS and to organize into protein-rich and dilute phases both in vivo and in vitro.Such a kind of phase separation of proteins plays an important role in a wide range of cellular processes,such as the formation of membraneless organelles(MLOs),signaling transduction,intracellular organization,chromatin organization,etc.In recent years,there appeared a great number of theoretical analysis,computational simulation and experimental research focusing on the physical principles of LLPS.In this article,the theoretical and computational simulation methods for the LLPS are briefly reviewed.To elucidate the physical principle of LLPS and to understand the phase behaviors of the proteins,biophysicists have introduced the concepts and theories from statistical mechanics and polymer sciences.Flory-Huggins theory and its extensions,such as mean-field model,random phase approximation(RPA)and field theory simulations,can conduce to understanding the phase diagram of the LLPS.To reveal the hidden principles in the sequence-dependent phase behaviors of different biomolecular condensates,different simulation methods including lattice models,off-lattice coarse-grained models,and all-atom simulations are introduced to perform computer simulations.By reducing the conformational space of the proteins,lattice models can capture the key points in LLPS and simplify the computations.In the off-lattice models,a polypeptide can be coarse-grained as connected particles representing repeated short peptide fragments.Allatom simulations can describe the structure of proteins at a higher resolution but consume higher computationpower.Multi-scale simulation may provide the key to understanding LLPS at both high computational efficiency and high accuracy.With these methods,we can elucidate the sequence-dependent phase behaviors of proteins at different resolutions.To sum up,it is necessary to choose the appropriate method to model LLPS processes according to the interactions within the molecules and the specific phase behaviors of the system.The simulations of LLPS can facilitate the comprehensive understanding of the key features which regulate the membraneless compartmentalization in cell biology and shed light on the design of artificial cells and the control of neurodegeneration.