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Review
. 2023 Aug:75:102333.
doi: 10.1016/j.cbpa.2023.102333. Epub 2023 May 31.

Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Beata Szała-Mendyk  1 , Tien Minh Phan  2 , Priyesh Mohanty  3 , Jeetain Mittal  4
Affiliations
Review

Challenges in studying the liquid-to-solid phase transitions of proteins using computer simulations

Beata Szała-Mendyk et al. Curr Opin Chem Biol. 2023 Aug.

Abstract

"Membraneless organelles," also referred to as biomolecular condensates, perform a variety of cellular functions and their dysregulation is implicated in cancer and neurodegeneration. In the last two decades, liquid-liquid phase separation (LLPS) of intrinsically disordered and multidomain proteins has emerged as a plausible mechanism underlying the formation of various biomolecular condensates. Further, the occurrence of liquid-to-solid transitions within liquid-like condensates may give rise to amyloid structures, implying a biophysical link between phase separation and protein aggregation. Despite significant advances, uncovering the microscopic details of liquid-to-solid phase transitions using experiments remains a considerable challenge and presents an exciting opportunity for the development of computational models which provide valuable, complementary insights into the underlying phenomenon. In this review, we first highlight recent biophysical studies which provide new insights into the molecular mechanisms underlying liquid-to-solid (fibril) phase transitions of folded, disordered and multi-domain proteins. Next, we summarize the range of computational models used to study protein aggregation and phase separation. Finally, we discuss recent computational approaches which attempt to capture the underlying physics of liquid-to-solid transitions along with their merits and shortcomings.

Keywords: Amyloid fibrils; Liquid-liquid phase separation (LLPS); Liquid-to-solid transition (LST); Molecular dynamics (MD) simulation.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1:
Figure 1:
Relationship between LLPS and fibril fromation. (a) At a given temperature, liquid-liquid phase separation is delineated by a coexistence curve or binodal. Phase separation of any concentration above the saturation concentration (Csat) manifests as liquid droplets with a higher concentration (Cdense). (b) Protein aggregation typically shows a sigmoidal curve of growth kinetics, where two relatively flat regions (lag phase and plateau phase, respectively) are connected by a steep transition zone (growth phase). In the lag phase, partially folded proteins associate to form primary nuclei. As nuclei reach the critical size, small fibrils emerge and elongate (the growth phase). Secondary processes, such as lateral growth, association, and dissociation of unmatured fibrils, also occur in this phase. When the monomer concentration reaches equilibrium, the system enters the plateau phase. (c) A liquid-to-solid transition (LST) occurs during droplet maturation with the emergence of hydrophobic cores forming from catalytic activities on the droplet interface. The fibril structures were generated using the CreateFibril tool [11].
Figure 2:
Figure 2:
Interaction modes contribute to protein phase separation and protein aggregation. (a) Liquid-liquid phase separation is stabilized by various intermolecular interactions, including π − π stacking, cation-π, salt bridges, hydrophobic interactions, and hydrogen bonds. (b) In amyloidogenic aggregation, backbone hydrogen bonds are essential for maintaining the secondary and tertiary structures of proteins and protein-protein interactions. Additionally, side-chain interactions involving different interaction modes can further enable the formation of hydrophobic cores, stabilize the structure of the protein and facilitate protein aggregation.
Figure 3:
Figure 3:
Computational models for the study of protein phase separation, protein aggregation, and liquid-to-solid-transition at various time scales and model resolutions. (a) AA slab simulation was utilized to explore interaction modes, and CG simulations using a re-balanced Martini model were employed to study dynamic materials properties of proteins within the condensed phase. CG slab simulations using a sequence-dependent one-bead-per-residue model were applied to establish one-phase and two-phase regimes of the phase diagram. (b) Recent computational work on liquid-to-solid transition: a phenomenological CG peptide model was used to study general properties of LLPS and amyloid aggregation, a one-bead-per-residue CG model with inter-peptide β-sheet formation was applied to explore the role of RNA on the aging of biomolecular condensate, and a CG multidomain model was developed to explore structural properties within FUS condensate. (c) Different model resolutions were employed to study different phases of amyloid aggregation ranging from explicit solvent atomistic simulation to sequence-dependent near atomic four-bead-per-residue models, to phenomenological models with coarser graining varying from three- and two-bead-per-residue to one-bead-per-protein. It should be noted that the CG models used to study fibril formation can also be used to study the early stages of protein aggregation such as intramolecular conformational changes and nucleation events [81, 86]. Images of computational models were adapted with permission under the Creative Commons Attribution License (CC BY 4.0) [72, 87, 79, 88], Creative Commons Attribution License (CC BY 3.0) [89], Copyright 2022 Biophysical Society [90], Copyright 2020 American Chemical Society [91], Copyright 2010 Wiley-Liss, Inc. [92], and under AIP Publishing [93, 75, 94].
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References

    1. Ross CA and Poirier MA. What is the role of protein aggregation in neurodegeneration? Nat. Rev. Mol. Cell Biol, 6:891–898, 2005. - PubMed
    1. Mohanty P, Kapoor UU, Sundaravadivelu Devarajan D, Phan TM, Rizuan A, and Mittal J. Principles governing the phase separation of multidomain proteins. Biochemistry, 61:2443–2455, 2022. - PMC - PubMed
    1. Alberti S and Hyman AA. Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat. Rev. Mol. Cell Biol, 22:196–213, 2021. - PubMed
    1. Shin Y and Brangwynne CP. Liquid phase condensation in cell physiology and disease. Science, 357:eaaf4382, 2017. - PubMed
    1. Babinchak WM and Surewicz WK. Liquid-liquid phase separation and its mechanistic role in pathological protein aggregation. J. Mol. Biol, 432:1910–1925, 2020. - PMC - PubMed

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