scholarly journals Kinetic interplay between droplet maturation and coalescence modulates shape of aged protein condensates

2021 ◽  
Author(s):  
Adiran Garaizar Suarez ◽  
Jorge R Espinosa ◽  
Jerelle Joseph ◽  
Rosana Collepardo-Guevara
Keyword(s):  
Protein Interactions ◽  
Interaction Strength ◽  
Potential Of Mean Force ◽  
Rate Of Change ◽  
Coarse Grained ◽  
Growth Stages ◽  
Coarse Grained Model ◽  
Condensate Formation ◽  
Β Sheets ◽  
Over Time

Biomolecular condensates formed by the process of liquid–liquid phase separation (LLPS) play diverse roles inside cells, from spatiotemporal compartmentalisation to speeding up chemical reactions. Upon maturation, the liquid-like properties of condensates, which underpin their functions, are gradually lost, eventually giving rise to solid-like states with potential pathological implications. Enhancement of inter-protein interactions is one of the main mechanisms suggested to trigger the formation of solid-like condensates. To gain a molecular-level understanding of how the accumulation of stronger interactions among proteins inside condensates affect the kinetic and thermodynamic properties of biomolecular condensates, and their shapes over time, we develop a tailored coarse-grained model of proteins that transition from establishing weak to stronger inter-protein interactions inside condensates. Our simulations reveal that the fast accumulation of strongly binding proteins during the nucleation and growth stages of condensate formation results in aspherical solid-like condensates. In contrast, when strong inter-protein interactions appear only after the equilibrium condensate has been formed, or when they accumulate slowly over time, with respect to the time needed for droplets to fuse and grow, spherical solid-like droplets emerge. By conducting atomistic potential-of-mean-force simulations of NUP-98 peptides —prone to forming inter-protein β-sheets— we observe that formation of inter-peptide β-sheets increases the strength of the interactions consistently with the loss of liquid-like condensate properties we observe at the coarse-grained level. Overall, our work aids in elucidating fundamental molecular, kinetic, and thermodynamic mechanisms linking the rate of change in protein interaction strength to condensate shape and maturation during ageing.

Modeling lipid raft domains containing a mono-unsaturated phosphatidylethanolamine species

RSC Advances ◽  
2015 ◽  
Vol 5 (47) ◽  
pp. 37102-37111 ◽  
Author(s):  
M. Ferraro ◽  
M. Masetti ◽  
M. Recanatini ◽  
A. Cavalli ◽  
G. Bottegoni
Keyword(s):  
Membrane Protein ◽  
Lipid Rafts ◽  
Protein Interactions ◽  
Lipid Raft ◽  
Coarse Grained ◽  
Coarse Grained Model ◽  
Raft Domains

An advanced coarse-grained model for “atypical” lipid rafts was built and validated to be employed in studies of membrane-protein interactions.

scholarly journals Simulation of Defects, Flexibility and Rupture in Biopolymer Networks

2021 ◽  
Author(s):  
Matthew H. J. Bailey ◽  
Mark Wilson
Keyword(s):  
Collagen Iv ◽  
Coarse Grained ◽  
Finite Width ◽  
Coarse Grained Model ◽  
Over Time ◽  
Hexagonal Network

Networks of biopolymers occur often in nature, and are vulnerable to damage over time. In this work, a coarse grained model of collagen IV molecules is applied in a 2D hexagonal network and the mechanisms by which these networks can rupture are explored. The networks are stretched linearly in order to study their structural limits and mechanism of rupture over timescale of up to 100 microseconds. Metrics are developed to track the damage networks suffer over time, and qualitatively analyse ruptures that occur. Further simulations repeatedly stretch the networks sinusoidally to mimic the in vivo strains. Defects of increasing levels of complexity are introduced into an ordered network, and their effect on the rupturing behaviour of the biopolymer networks studied. The effect of introducing holes of varying size in the network, as well as strips of finite width to mimic surgical damage are studied. These demonstrate the importance of the flexibility of the networks to preventing damage.

scholarly journals Importance of Interface in the Coarse-Grained Model of CNT /Epoxy Nanocomposites

Nanomaterials ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 1479 ◽  
Author(s):  
Ke Duan ◽  
Li Li ◽  
Fei Wang ◽  
Weishuang Meng ◽  
Yujin Hu ◽  
...  
Keyword(s):  
Polymer Nanocomposites ◽  
Cohesive Energy ◽  
Load Transfer ◽  
Interaction Strength ◽  
Coarse Graining ◽  
Thermomechanical Properties ◽  
Coarse Grained ◽  
Strength Parameter ◽  
Coarse Grained Model ◽  
Transfer Behavior

Interface interactions play a crucial role in determining the thermomechanical properties of carbon nanotubes (CNTs)/polymer nanocomposites. They are, however, poorly treated in the current multi-scale coarse-grained (CG) models. To develop suitable CG models of CNTs/polymer nanocomposites, we demonstrate the importance of two aspects for the first time, that is, preserving the interfacial cohesive energy and reproducing the interface load transfer behavior of all-atomistic (AA) systems. Our simulation results indicate that, for CNTs/polymer nanocomposites, the interface cohesive energy and the interface load transfer of CG models are generally inconsistent with their AA counterparts, revealing significant deviations in their predicted mechanical properties. Fortunately, such inconsistency can be “corrected” by phenomenologically adjusting the cohesive interaction strength parameter of the interface LJ potentials in conjunction with choosing a reasonable degree of coarse-graining of incorporated CNTs. We believe that the problem studied here is general for the development of the CG models of nanocomposites, and the proposed strategy used in present work may be applied to polymer nanocomposites reinforced by other nanofillers.

scholarly journals Molecular determinants of the interactions between proteins and ssDNA

2015 ◽  
Vol 112 (16) ◽  
pp. 5033-5038 ◽  
Author(s):  
Garima Mishra ◽  
Yaakov Levy
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Binding Pocket ◽  
Dna Bases ◽  
Coarse Grained ◽  
Binding Modes ◽  
Ssdna Binding ◽  
Coarse Grained Model ◽  
Molecular Determinants ◽  
Ssdna Binding Proteins

ssDNA binding proteins (SSBs) protect ssDNA from chemical and enzymatic assault that can derail DNA processing machinery. Complexes between SSBs and ssDNA are often highly stable, but predicting their structures is challenging, mostly because of the inherent flexibility of ssDNA and the geometric and energetic complexity of the interfaces that it forms. Here, we report a newly developed coarse-grained model to predict the structure of SSB–ssDNA complexes. The model is successfully applied to predict the binding modes of six SSBs with ssDNA strands of lengths of 6–65 nt. In addition to charge–charge interactions (which are often central to governing protein interactions with nucleic acids by means of electrostatic complementarity), an essential energetic term to predict SSB–ssDNA complexes is the interactions between aromatic residues and DNA bases. For some systems, flexibility is required from not only the ssDNA but also, the SSB to allow it to undergo conformational changes and the penetration of the ssDNA into its binding pocket. The association mechanisms can be quite varied, and in several cases, they involve the ssDNA sliding along the protein surface. The binding mechanism suggests that coarse-grained models are appropriate to study the motion of SSBs along ssDNA, which is expected to be central to the function carried out by the SSBs.

scholarly journals Kinetic frustration by limited bond availability controls the LAT protein condensation phase transition on membranes

2021 ◽  
Author(s):  
Simou Sun ◽  
Trevor GrandPre ◽  
David T. Limmer ◽  
Jay T. Groves
Keyword(s):  
Phase Transition ◽  
T Cell Activation ◽  
Protein Interactions ◽  
Cell Activation ◽  
Coarse Grained ◽  
Structural Basis ◽  
Protein Protein Interactions ◽  
Kinetic Measurements ◽  
Coarse Grained Model ◽  
Intrinsically Disordered

AbstractLAT is a membrane-linked scaffold protein that undergoes a phase transition to form a two-dimensional protein condensate on the membrane during T cell activation. Governed by tyrosine phosphorylation, LAT recruits various proteins that ultimately enable condensation through a percolation network of discrete and selective protein-protein interactions. Here we describe detailed kinetic measurements of the phase transition, along with coarse-grained model simulations, that reveal LAT condensation is kinetically frustrated by the availability of bonds to form the network. Unlike typical miscibility transitions in which compact domains may coexist at equilibrium, the LAT condensates are dynamically arrested in extended states, kinetically trapped out of equilibrium. Modeling identifies the structural basis for this kinetic arrest as the formation of spindle arrangements, favored by limited multivalent binding interactions along the flexible, intrinsically disordered LAT protein. These results reveal how local factors controlling the kinetics of LAT condensation enable formation of different, stable condensates, which may ultimately coexist within the cell.

scholarly journals Quantitative analysis of membrane-mediated interactions and aggregation of flexible peripheral proteins orchestrating large-scale membrane remodeling

2021 ◽  
Author(s):  
Mohsen Sadeghi ◽  
Frank Noe
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Effective Interaction ◽  
Bilayer Membrane ◽  
Coarse Grained ◽  
Membrane Remodeling ◽  
Coarse Grained Model ◽  
Sequence Of Events ◽  
Peripheral Proteins ◽  
The Stability

Shaping and remodeling of biomembranes is essential for cellular trafficking, with membrane-binding peripheral proteins playing the key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to clusters or aggregates of many proteins whose interactions may be direct or mediated via the membrane. While computer simulation could be an important tool to disentangle these interactions and understand what drives cooperative protein interactions in membrane remodeling, this has so far been extremely challenging: protein-membrane systems involve time- and lengthscales that make detailed atomistic simulations impractical, while most coarse-grained models lack the degree of detail needed to resolve the dynamics and physical effect of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible membrane-bound proteins. We show how this model can be parameterized based on local curvatures, protein flexibility, and the in-plane dynamics of proteins. We measure the effective interaction potential for the membrane-mediated interactions between peripheral proteins. Furthermore, we investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the protein plays a deciding role in highly selective macroscopic aggregation behavior. Finally, we present large-scale simulations of membrane tubulation, and discuss the sequence of events and the stability of intermediates.

scholarly journals Liquid network connectivity regulates the stability and composition of biomolecular condensates with many components

2020 ◽  
Vol 117 (24) ◽  
pp. 13238-13247 ◽  
Author(s):  
Jorge R. Espinosa ◽  
Jerelle A. Joseph ◽  
Ignacio Sanchez-Burgos ◽  
Adiran Garaizar ◽  
Daan Frenkel ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Critical Points ◽  
Network Connectivity ◽  
Coarse Grained ◽  
Physical Parameters ◽  
Protein Protein Interactions ◽  
Coarse Grained Model ◽  
Bond Network ◽  
The Stability ◽  
Liquid Liquid Phase Separation

One of the key mechanisms used by cells to control the spatiotemporal organization of their many components is the formation and dissolution of biomolecular condensates through liquid–liquid phase separation (LLPS). Using a minimal coarse-grained model that allows us to simulate thousands of interacting multivalent proteins, we investigate the physical parameters dictating the stability and composition of multicomponent biomolecular condensates. We demonstrate that the molecular connectivity of the condensed-liquid network—i.e., the number of weak attractive protein–protein interactions per unit of volume—determines the stability (e.g., in temperature, pH, salt concentration) of multicomponent condensates, where stability is positively correlated with connectivity. While the connectivity of scaffolds (biomolecules essential for LLPS) dominates the phase landscape, introduction of clients (species recruited via scaffold–client interactions) fine-tunes it by transforming the scaffold–scaffold bond network. Whereas low-valency clients that compete for scaffold–scaffold binding sites decrease connectivity and stability, those that bind to alternate scaffold sites not required for LLPS or that have higher-than-scaffold valencies form additional scaffold–client–scaffold bridges increasing stability. Proteins that establish more connections (via increased valencies, promiscuous binding, and topologies that enable multivalent interactions) support the stability of and are enriched within multicomponent condensates. Importantly, proteins that increase the connectivity of multicomponent condensates have higher critical points as pure systems or, if pure LLPS is unfeasible, as binary scaffold–client mixtures. Hence, critical points of accessible systems (i.e., with just a few components) might serve as a unified thermodynamic parameter to predict the composition of multicomponent condensates.

scholarly journals Coarse-grained Force Fields from the Perspective of Statistical Mechanics: Better Understanding the Origins of a MARTINI Hangover

2020 ◽  
Author(s):  
Zack Jarin ◽  
James Newhouse ◽  
Gregory A. Voth
Keyword(s):  
Statistical Mechanics ◽  
Lipid Bilayers ◽  
Potential Of Mean Force ◽  
Distribution Functions ◽  
Coarse Grained ◽  
Test Case ◽  
Top Down ◽  
Coarse Grained Model ◽  
Potentials Of Mean Force ◽  
Dynamics Models

AbstractThe popular MARTINI coarse-grained model is used as a test case to analyze the adherence of top-down coarse-grained molecular dynamics models (i.e., models primarily parameterized to match experimental results) to the known features of statistical mechanics for the underlying all-atom representations. Specifically, the temperature dependence of various pair distribution functions, and hence their underlying potentials of mean force via the reversible work theorem, are compared between MARTINI 2.0, Dry MARTINI, and all-atom simulations mapped onto equivalent coarse-grained sites for certain lipid bilayers. It is found that the MARTINI models do not completely capture the lipid structure seen in atomistic simulations as projected onto the coarse-grained mappings, and that issues of accuracy and temperature transferability arise due to an incorrect enthalpy-entropy decomposition of these potentials of mean force. The potential of mean force for the association of two amphipathic helices in a lipid bilayer is also calculated and, especially at shorter ranges, the MARTINI and all-atom projection results differ substantially. The former is much less repulsive and hence will lead to a higher probability of MARTINI helix association in the MARTINI bilayer than occurs in the actual all-atom case. Additionally, the bilayer height fluctuation spectra are calculated for the MARTINI model and – compared to the all-atom results – it is found that the magnitude of thermally averaged amplitudes at intermediate length scales is quite different, pointing to a number of possible consequences for realistic modeling of membrane processes. Taken as a whole, the results presented here can point the way for future coarse-grained model parameterization efforts that might bring top-down coarse-grained models into better agreement with the statistical mechanics of the actual all-atom systems they aspire to represent.

scholarly journals Coarse-Grained Model for Colloidal Protein Interactions, B22, and Protein Cluster Formation

2013 ◽  
Vol 117 (50) ◽  
pp. 16013-16028 ◽  
Author(s):  
Marco A. Blanco ◽  
Erinc Sahin ◽  
Anne S. Robinson ◽  
Christopher J. Roberts
Keyword(s):  
Protein Interactions ◽  
Cluster Formation ◽  
Coarse Grained ◽  
Protein Cluster ◽  
Coarse Grained Model

scholarly journals Quantitative analysis of membrane-mediated interactions and aggregation of flexible peripheral proteins orchestrating large-scale membrane remodeling

2021 ◽  
Author(s):  
Mohsen Sadeghi ◽  
Frank Noé
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Effective Interaction ◽  
Bilayer Membrane ◽  
Coarse Grained ◽  
Membrane Remodeling ◽  
Coarse Grained Model ◽  
Sequence Of Events ◽  
Peripheral Proteins ◽  
The Stability

Abstract Shaping and remodeling of biomembranes is essential for cellular trafficking, with membrane-binding peripheral proteins playing the key role in it. Significant membrane remodeling as in endo- and exocytosis is often due to clusters or aggregates of many proteins whose interactions may be direct or mediated via the membrane. While computer simulation could be an important tool to disentangle these interactions and understand what drives cooperative protein interactions in membrane remodeling, this has so far been extremely challenging: protein-membrane systems involve time- and lengthscales that make detailed atomistic simulations impractical, while most coarse-grained models lack the degree of detail needed to resolve the dynamics and physical effect of protein and membrane flexibility. Here, we develop a coarse-grained model of the bilayer membrane bestrewed with rotationally-symmetric flexible membrane-bound proteins. We show how this model can be parameterized based on local curvatures, protein flexibility, and the in-plane dynamics of proteins. We measure the effective interaction potential for the membrane-mediated interactions between peripheral proteins. Furthermore, we investigate the kinetics, equilibrium distributions, and the free energy landscape governing the formation and break-up of protein clusters on the surface of the membrane. We demonstrate how the flexibility of the protein plays a deciding role in highly selective macroscopic aggregation behavior. Finally, we present large-scale simulations of membrane tubulation, and discuss the sequence of events and the stability of intermediates.

Sign in / Sign up

Export Citation Format

Share Document