Dataset Information

Coarse-Grained Simulation of Full-Length Integrin Activation.

ABSTRACT: Integrin conformational dynamics are critical to their receptor and signaling functions in many cellular processes, including spreading, adhesion, and migration. However, assessing integrin conformations is both experimentally and computationally challenging because of limitations in resolution and dynamic sampling. Thus, structural changes that underlie transitions between conformations are largely unknown. Here, focusing on integrin ?v?3, we developed a modified form of the coarse-grained heterogeneous elastic network model (hENM), which allows sampling conformations at the onset of activation by formally separating local fluctuations from global motions. Both local fluctuations and global motions are extracted from all-atom molecular dynamics simulations of the full-length ?v?3 bent integrin conformer, but whereas the former are incorporated in the hENM as effective harmonic interactions between groups of residues, the latter emerge by systematically identifying and treating weak interactions between long-distance domains with flexible and anharmonic connections. The new hENM model allows integrins and single-point mutant integrins to explore various conformational states, including the initiation of separation between ?- and ?-subunit cytoplasmic regions, headpiece extension, and legs opening.

SUBMITTER: Bidone TC

PROVIDER: S-EPMC6428961 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Coarse-Grained Simulation of Full-Length Integrin Activation.

Bidone Tamara C TC Polley Anirban A Jin Jaehyeok J Driscoll Tristan T Iwamoto Daniel V DV Calderwood David A DA Schwartz Martin A MA Voth Gregory A GA

Biophysical journal 20190222 6

Integrin conformational dynamics are critical to their receptor and signaling functions in many cellular processes, including spreading, adhesion, and migration. However, assessing integrin conformations is both experimentally and computationally challenging because of limitations in resolution and dynamic sampling. Thus, structural changes that underlie transitions between conformations are largely unknown. Here, focusing on integrin αvβ<sub>3</sub>, we developed a modified form of the coarse-g ...[more]

PMID: 30851876

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Project description:Disordered proteins and nucleic acids can condense into droplets that resemble the membraneless organelles observed in living cells. MD simulations offer a unique tool to characterize the molecular interactions governing the formation of these biomolecular condensates, their physicochemical properties, and the factors controlling their composition and size. However, biopolymer condensation depends sensitively on the balance between different energetic and entropic contributions. Here, we develop a general strategy to fine-tune the potential energy function for molecular dynamics simulations of biopolymer phase separation. We rebalance protein-protein interactions against solvation and entropic contributions to match the excess free energy of transferring proteins between dilute solution and condensate. We illustrate this formalism by simulating liquid droplet formation of the FUS low-complexity domain (LCD) with a rebalanced MARTINI model. By scaling the strength of the nonbonded interactions in the coarse-grained MARTINI potential energy function, we map out a phase diagram in the plane of protein concentration and interaction strength. Above a critical scaling factor of αc ≈ 0.6, FUS-LCD condensation is observed, where α = 1 and 0 correspond to full and repulsive interactions in the MARTINI model. For a scaling factor α = 0.65, we recover experimental densities of the dilute and dense phases, and thus the excess protein transfer free energy into the droplet and the saturation concentration where FUS-LCD condenses. In the region of phase separation, we simulate FUS-LCD droplets of four different sizes in stable equilibrium with the dilute phase and slabs of condensed FUS-LCD for tens of microseconds, and over one millisecond in aggregate. We determine surface tensions in the range of 0.01-0.4 mN/m from the fluctuations of the droplet shape and from the capillary-wave-like broadening of the interface between the two phases. From the dynamics of the protein end-to-end distance, we estimate shear viscosities from 0.001 to 0.02 Pa s for the FUS-LCD droplets with scaling factors α in the range of 0.625-0.75, where we observe liquid droplets. Significant hydration of the interior of the droplets keeps the proteins mobile and the droplets fluid.

Dataset Information

Coarse-Grained Simulation of Full-Length Integrin Activation.

Publications

Coarse-Grained Simulation of Full-Length Integrin Activation.

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