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Force-induced unzipping transitions in an athermal crowded environment.

ABSTRACT: Using theoretical arguments and extensive Monte Carlo (MC) simulations of a coarse-grained three-dimensional off-lattice model of a ?-hairpin, we demonstrate that the equilibrium critical force, Fc, needed to unfold the biopolymer increases nonlinearly with increasing volume fraction occupied by the spherical macromolecular crowding agent. Both scaling arguments and MC simulations show that the critical force increases as Fc ? ?c(?). The exponent ? is linked to the Flory exponent relating the size of the unfolded state of the biopolymer and the number of amino acids. The predicted power law dependence is confirmed in simulations of the dependence of the isothermal extensibility and the fraction of native contacts on ?c. We also show using MC simulations that Fc is linearly dependent on the average osmotic pressure (P) exerted by the crowding agents on the ?-hairpin. The highly significant linear correlation coefficient of 0.99657 between Fc and P makes it straightforward to predict the dependence of the critical force on the density of crowders. Our predictions are amenable to experimental verification using laser optical tweezers.

SUBMITTER: Pincus DL

PROVIDER: S-EPMC3808530 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Force-induced unzipping transitions in an athermal crowded environment.

Pincus David L DL Thirumalai D D

The journal of physical chemistry. B 20130712 42

Using theoretical arguments and extensive Monte Carlo (MC) simulations of a coarse-grained three-dimensional off-lattice model of a β-hairpin, we demonstrate that the equilibrium critical force, Fc, needed to unfold the biopolymer increases nonlinearly with increasing volume fraction occupied by the spherical macromolecular crowding agent. Both scaling arguments and MC simulations show that the critical force increases as Fc ≈ φc(α). The exponent α is linked to the Flory exponent relating the si ...[more]

PMID: 23789729

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Project description:The high concentration of macromolecules in the crowded cellular interior influences different thermodynamic and kinetic properties of proteins, including their structural stabilities, intermolecular binding affinities and enzymatic rates. Moreover, various structural biology methods, such as NMR or different spectroscopies, typically involve samples with relatively high protein concentration. Due to large sampling requirements, however, the accuracy of classical molecular dynamics (MD) simulations in capturing protein behavior at high concentration still remains largely untested. Here, we use explicit-solvent MD simulations and a total of 6.4 µs of simulated time to study wild-type (folded) and oxidatively damaged (unfolded) forms of villin headpiece at 6 mM and 9.2 mM protein concentration. We first perform an exhaustive set of simulations with multiple protein molecules in the simulation box using GROMOS 45a3 and 54a7 force fields together with different types of electrostatics treatment and solution ionic strengths. Surprisingly, the two villin headpiece variants exhibit similar aggregation behavior, despite the fact that their estimated aggregation propensities markedly differ. Importantly, regardless of the simulation protocol applied, wild-type villin headpiece consistently aggregates even under conditions at which it is experimentally known to be soluble. We demonstrate that aggregation is accompanied by a large decrease in the total potential energy, with not only hydrophobic, but also polar residues and backbone contributing substantially. The same effect is directly observed for two other major atomistic force fields (AMBER99SB-ILDN and CHARMM22-CMAP) as well as indirectly shown for additional two (AMBER94, OPLS-AAL), and is possibly due to a general overestimation of the potential energy of protein-protein interactions at the expense of water-water and water-protein interactions. Overall, our results suggest that current MD force fields may distort the picture of protein behavior in biologically relevant crowded environments.

Dataset Information

Force-induced unzipping transitions in an athermal crowded environment.

Publications

Force-induced unzipping transitions in an athermal crowded environment.

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