On the electrostatic component of protein-protein binding free energy

Talley, Kemper; Ng, Carmen S.; Shoppell, Michael; Kundrotas, Petras J.; Alexov, Emil

doi:10.1186/1757-5036-1-2

Cited by 52 publications

(68 citation statements)

References 86 publications

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“…With our model, ΔG bind,elec,uncrowded was found to be 0.5 kcal/mol, suggesting that the electrostatic component of binding in this system (in pure aqueous solvent) is neither strongly favorable nor unfavorable, in qualitative agreement with previous work using quantitatively different parameters [70]. Given that the electrostatic binding free energies between proteins are generally quite unfavorable with models using an internal dielectric constant of 4 [71], our value supports the accepted view that electrostatics play an important role in this system.…”

Section: Resultssupporting

confidence: 86%

The Effect of Macromolecular Crowding on the Electrostatic Component of Barnase–Barstar Binding: A Computational, Implicit Solvent-Based Study

Qi¹,

Nakka²,

Chen³

et al. 2014

PLoS ONE

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Macromolecular crowding within the cell can impact both protein folding and binding. Earlier models of cellular crowding focused on the excluded volume, entropic effect of crowding agents, which generally favors compact protein states. Recently, other effects of crowding have been explored, including enthalpically-related crowder–protein interactions and changes in solvation properties. In this work, we explore the effects of macromolecular crowding on the electrostatic desolvation and solvent-screened interaction components of protein–protein binding. Our simple model enables us to focus exclusively on the electrostatic effects of water depletion on protein binding due to crowding, providing us with the ability to systematically analyze and quantify these potentially intuitive effects. We use the barnase–barstar complex as a model system and randomly placed, uncharged spheres within implicit solvent to model crowding in an aqueous environment. On average, we find that the desolvation free energy penalties incurred by partners upon binding are lowered in a crowded environment and solvent-screened interactions are amplified. At a constant crowder density (fraction of total available volume occupied by crowders), this effect generally increases as the radius of model crowders decreases, but the strength and nature of this trend can depend on the water probe radius used to generate the molecular surface in the continuum model. In general, there is huge variation in desolvation penalties as a function of the random crowder positions. Results with explicit model crowders can be qualitatively similar to those using a lowered “effective” solvent dielectric to account for crowding, although the “best” effective dielectric constant will likely depend on multiple system properties. Taken together, this work systematically demonstrates, quantifies, and analyzes qualitative intuition-based insights into the effects of water depletion due to crowding on the electrostatic component of protein binding, and it provides an initial framework for future analyses.

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Section: Resultssupporting

confidence: 86%

The Effect of Macromolecular Crowding on the Electrostatic Component of Barnase–Barstar Binding: A Computational, Implicit Solvent-Based Study

Qi¹,

Nakka²,

Chen³

et al. 2014

PLoS ONE

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“…Since homodimeric proteins are made of two identical chains carrying the same net charge, it is expected that in most cases the electrostatic forces will oppose binding [20]. However, homodimerization is frequently found to be necessary for the function of many proteins [21,22,23,24].…”

Section: Introductionmentioning

confidence: 99%

On the electrostatic properties of homodimeric proteins

Campbell

Petukh

Alexov

et al. 2014

J. Theor. Comput. Chem.

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A large fraction of proteins function as homodimers, but it is not always clear why the dimerization is important for functionality since frequently each monomer possesses a distinctive active site. Recent work (PLoS Computational Biology, 9(2), e1002924) indicates that homodimerization may be important for forming an electrostatic funnel in the spermine synthase homodimer which guides changed substrates toward the active centers. This prompted us to investigate the electrostatic properties of a large set of homodimeric proteins and resulted in an observation that in a vast majority of the cases the dimerization indeed results in specific electrostatic features, although not necessarily in an electrostatic funnel. It is demonstrated that the electrostatic dipole moment of the dimer is predominantly perpendicular to the axis connecting the centers of the mass of the monomers. In addition, the surface points with highest potential are located in the proximity of the interfacial plane of the homodimeric complexes. These findings indicate that frequently homodimerization provides specific electrostatic features needed for the function of proteins.

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“…The overall proton uptake/release induced by protein-ligand association originates from individual pKa shifts of titratable groups induced by the complex formation [28–30]. Therefore successful pKa calculations on the pKa’s of the titratable groups before and after the binding would be sufficient to determine the proton uptake/release as a function of the pH of the solution and to obtain the pH-dependence of the binding free energy [27, 31].…”

Section: Introductionmentioning

confidence: 99%

In Silico Investigation of pH-Dependence of Prolactin and Human Growth Hormone Binding to Human Prolactin Receptor

Wang

Witham

Zhang

et al. 2013

Commun. comput. phys.

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Experimental data shows that the binding of human prolactin (hPRL) to human prolactin receptor (hPRLr-ECD) is strongly pH-dependent, while the binding of the same receptor to human growth hormone (hGH) is pH-independent. Here we carry in silico analysis of the molecular effects causing such a difference and reveal the role of individual amino acids. It is shown that the computational modeling correctly predicts experimentally determined pKa’s of histidine residues in an unbound state in the majority of the cases and the pH-dependence of the binding free energy. Structural analysis carried in conjunction with calculated pH-dependence of the binding revealed that the main reason for pH-dependence of the binding of hPRL-hPRLr-ECD is a number of salt- bridges across the interface of the complex, while no salt-bridges are formed in the hGH-hPRlr-ECD. Specifically, most of the salt-bridges involve histidine residues and this is the reason for the pH-dependence across a physiological range of pH. The analysis not only revealed the molecular mechanism of the pH-dependence of the hPRL-hPRLr-ECD, but also provided critical insight into the underlying physic-chemical mechanism.

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On the electrostatic component of protein-protein binding free energy

Cited by 52 publications

References 86 publications

The Effect of Macromolecular Crowding on the Electrostatic Component of Barnase–Barstar Binding: A Computational, Implicit Solvent-Based Study

The Effect of Macromolecular Crowding on the Electrostatic Component of Barnase–Barstar Binding: A Computational, Implicit Solvent-Based Study

On the electrostatic properties of homodimeric proteins

In Silico Investigation of pH-Dependence of Prolactin and Human Growth Hormone Binding to Human Prolactin Receptor

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