Contrasting Factors on the Kinetic Path to Protein Complex Formation Diminish the Effects of Crowding Agents

Phillip, Yael; Harel, Michal; Khait, Ruth; Qin, Sanbo; Zhou, Huan‐Xiang; Schreiber, Gideon

doi:10.1016/j.bpj.2012.08.009

Cited by 37 publications

(47 citation statements)

References 55 publications

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“…Therefore despite the presence of crowders the association would appear unimpeded. This prediction is confirmed by recent kinetic experiments under in vitro crowding and in living cells [50,51•]. …”

Section: Influence Of Cellular Environments On Association Kineticssupporting

confidence: 80%

Modeling protein association mechanisms and kinetics

Zhou

Bates

2013

Current Opinion in Structural Biology

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Substantial advances have been made in modeling protein association mechanisms and in calculating association rate constants (ka). We now have a clear understanding of the physical factors underlying the wide range of experimental ka values. Half of the association problem, where ka is limited by diffusion, is perhaps solved, and for the other half, where conformational changes become rate-limiting, a number of promising methods are being developed for ka calculations. Notably, the binding kinetics of disordered proteins are receiving growing attention, with “dock-and-coalescence” emerging as a general mechanism. Progress too has been made in the modeling of protein association kinetics under conditions mimicking the heterogeneous, crowded environments of cells, an endeavor that should ultimately lead to a better understanding of cellular functions.

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Section: Influence Of Cellular Environments On Association Kineticssupporting

confidence: 80%

Modeling protein association mechanisms and kinetics

Zhou

Bates

2013

Current Opinion in Structural Biology

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“…The effects of crowding on the association kinetics of the latter two systems have been investigated in recent experimental studies [8–10, 12–14]. …”

Section: Resultsmentioning

confidence: 99%

A method for computing association rate constants of atomistically represented proteins under macromolecular crowding

2012

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In cellular environments, two protein molecules on their way to form a specific complex encounter many bystander macromolecules. The latter molecules, or crowders, affect both the energetics of the interaction between the test molecules and the dynamics of their relative motion. In earlier work (Zhou and Szabo 1991 J. Chem. Phys. 95 5948-52), it has been shown that, in modeling the association kinetics of the test molecules, the presence of crowders can be accounted for by their energetic and dynamic effects. The recent development of the transient-complex theory for protein association in dilute solutions makes it possible to easily incorporate the energetic and dynamic effects of crowders. The transient complex refers to a late on-pathway intermediate, in which the two protein molecules have near-native relative separation and orientation but have yet to form the many short-range specific interactions of the native complex. The transient-complex theory predicts the association rate constant as ka = ka0exp (−ΔGel*/kBT), where ka0 is the “basal” rate constant for reaching the transient complex by unbiased diffusion, and the Boltzmann factors captures the influence of long-range electrostatic interactions between the protein molecules. Crowders slow down the diffusion, therefore reducing the basal rate constant (to kac0), and induce an effective interaction energy ΔGc. We show that the latter interaction energy for atomistic proteins in the presence of spherical crowders is “long”-ranged, allowing the association rate constant under crowding to be computed as kac = kac0exp[−(ΔGel* + ΔGc*)/kBT]. Applications demonstrate that this computational method allows for realistic modeling of protein association kinetics under crowding.

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“…Similar subtle effects of hard-core repulsion and soft attraction can be expected for protein binding stability under crowding. As for binding kinetics, these subtle effects on thermodynamics are further muddied by crowding effects on inter- and intra-protein dynamics [77]. All these complications highlight the importance of accurate modeling of protein-crowder interactions for capturing both the trends and the magnitudes of crowding effects on protein folding and binding.…”

Section: Varying Effects Of Protein-crowder Hard-core Repulsion and Smentioning

confidence: 99%

Protein folding, binding, and droplet formation in cell-like conditions

Qin

Zhou

2017

Current Opinion in Structural Biology

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The many bystander macromolecules in the crowded cellular environments present both steric repulsion and weak attraction to proteins undergoing folding or binding and hence impact the thermodynamic and kinetic properties of these processes. The weak not nonrandom binding with bystander macromolecules may facilitate subcellular localization and biological function. Weak binding also leads to the emergence of a protein-rich, droplet phase, which has been implicated in regulating a variety of cellular functions. All these important problems can now be addressed by realistic modeling of intermolecular interactions. Configurational sampling of concentrated protein solutions is an ongoing challenge.

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Contrasting Factors on the Kinetic Path to Protein Complex Formation Diminish the Effects of Crowding Agents

Cited by 37 publications

References 55 publications

Modeling protein association mechanisms and kinetics

Modeling protein association mechanisms and kinetics

A method for computing association rate constants of atomistically represented proteins under macromolecular crowding

Protein folding, binding, and droplet formation in cell-like conditions

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