Electrostatic Steering Accelerates C3d:CR2 Association

Mohan, Rohith R.; Huber, Gary L.; Morikis, Dimitrios

doi:10.1021/acs.jpcb.6b02095

Cited by 9 publications

(7 citation statements)

References 78 publications

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“…As a consequence, in the considered HEWL–NAG 3 case, one may expect (as we show further) only a weak dependence of the diffusional association rate constant on the solution ionic strength, unlike in molecular systems in which association is driven by either net charge–net charge attraction or net charge–net charge repulsion. There is a vast literature documenting the role of electrostatic interactions in the kinetics of molecular association. − …”

Section: Introductionmentioning

confidence: 99%

Does Ionic Screening Lower Activation Barriers for Conformational Transitions in Proteins?

Antosiewicz

Długosz

2018

J. Phys. Chem. B

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In this work, we investigated the kinetics of binding of hen egg-white lysozyme with tri-N-acetylglucosamine in aqueous solutions, at two values of pH, 3.2 and 11, as a function of ionic strength, by a stopped-flow method with tryptophyl fluorescence observation of the transients. We analyzed registered reaction progress curves by employing numerical integration of appropriate chemical master equations. We discriminated between several binding models and established that the process observed in experiments follows a two-step mechanism, composed of four elementary stages: diffusional formation of an encounter complex, dissociation of the encounter complex, conformational transition of the encounter complex to the final complex, and the reverse transformation, i.e., from the final complex to the encounter complex. We evaluated rate constants of these elementary stages and determined their dependencies on solution ionic strength. Regardless of solution pH, rate constants of both forward and reverse conformational transitions increase with an increasing ionic strength. This suggests that ionic screening of intramolecular electrostatic interactions may act to lower the activation barrier for conformational transition in proteins.

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Section: Introductionmentioning

confidence: 99%

Does Ionic Screening Lower Activation Barriers for Conformational Transitions in Proteins?

Antosiewicz

Długosz

2018

J. Phys. Chem. B

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“…In such a case every time molecules are pushed together, a hydrodynamic torque arises that rotate molecules allowing a better fit of their shapes. It was postulated that this coupling torque should influence the association kinetics similarly as it has been observed in the case of the electrostatic steering. − …”

Section: Discussionmentioning

confidence: 85%

“…Opposite net charges (monopoles) result in attraction of associating molecules, whereas the existence of molecular electric dipoles gives rise to electrostatic torques that will orient approaching molecules so that their dipole moments are antiparallel. More than three decades ago in order to name these fundamental effects, a concept of electrostatic steering was introduced. − There is a vast literature documenting the existence of electrostatic steering and its role in the kinetics of molecular association. − …”

Section: Introductionmentioning

confidence: 99%

Hydrodynamic Steering in Protein Association Revisited: Surprisingly Minuscule Effects of Considerable Torques

2017

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We investigate the previously postulated hydrodynamic steering phenomenon, resulting from complication of molecular shapes, its magnitude and possible relevance for protein-ligand and protein-protein diffusional encounters, and the kinetics of diffusion-controlled association. We consider effects of hydrodynamic interactions in a prototypical model system consisting of a cleft enzyme and an elongated substrate, and real protein-protein complexes, that of barnase and barstar, and human growth hormone and its binding protein. The kinetics of diffusional encounters is evaluated on the basis of rigid-body Brownian dynamics simulations in which hydrodynamic interactions between molecules are modeled using the bead-shell method for detailed description of molecular surfaces, and the first-passage-time approach. We show that magnitudes of steering torques resulting from the hydrodynamic coupling of associating molecules, evaluated for the studied systems on the basis of the Stokes-Einstein type relations for arbitrarily shaped rigid bodies, are comparable with magnitudes of torques resulting from electrostatic interactions of binding partners. Surprisingly, however, unlike in the case of electrostatic torques that strongly affect the diffusional encounter, overall effects of hydrodynamic steering torques on the association kinetics, while clearly discernible in Brownian dynamics simulations, are rather minute. We explain this result as a consequence of the thermal agitation of the binding partners. Our finding is relevant for the general understanding of a wide spectrum of molecular processes in solution but there is also a more practical aspect to it if one considers the low level of shape detail of models that are usually employed to evaluate hydrodynamic interactions in particle-based Stokesian and Brownian dynamics simulations of multicomponent biomolecular systems. Results described in the current work justify, in part at least, such a low-resolution description.

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“…Electrostatic hotspot analysis has been performed using the AESOP (Analysis of Electrostatic Similarities Of Proteins) code, developed by Morikis ( Kieslich et al, 2011b ; Harrison et al, 2017 ) and extensively employed for electrostatic analysis of proteins ( Kieslich et al, 2011a , Kieslich et al, 2011b ; Gorham et al, 2011a , Gorham et al, 2011b ; Harrison et al, 2015 ; Mohan et al, 2015 , Mohan et al, 2016 ; Zewde et al, 2018 ; Harrison and Morikis, 2019 ). AESOP enables the analysis of electrostatic hotspots through the calculation of an Electrostatic Similarity Indices (ESI), ( Kieslich and Morikis, 2012 ), which assesses the electrostatic potential upon perturbation (i.e., mutagenesis), identifying regions of high electrostatic similarity, or those regions least affected by perturbation.…”

Section: Computational Materials and Methodsmentioning

confidence: 99%

Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition

Narkhede

Gautam

Hsu

et al. 2021

Front. Mol. Biosci.

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Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we examine the role of the electrostatics in the selectivity of the smallpox protein SPICE and vaccinia protein VCP toward the human and bovine complement protein C3b, a key component of the complement immune response. Electrostatic calculations, in-silico alanine-scan and electrostatic hotspot analysis, as introduced by Kieslich and Morikis (PLoS Comput. Biol. 2012), are used to assess the electrostatic complementarity and to identify sites resistant to local perturbation where the electrostatic potential is likely to be evolutionary conserved. The calculations suggest that the bovine C3b is electrostatically prone to selectively bind its VCP ligand. On the other hand, the human isoform of C3b exhibits a lower electrostatic complementarity toward its SPICE ligand. Yet, the human C3b displays a highly preserved electrostatic core, which suggests that this isoform could be less selective in binding different ligands like SPICE and the human Factor H. This is supported by experimental cofactor activity assays revealing that the human C3b is prone to bind both SPICE and Factor H, which exhibit diverse electrostatic properties. Additional investigations considering mutants of SPICE and VCP that revert their selectivity reveal an “electrostatic switch” into the central modules of the ligands, supporting the critical role of the electrostatics in the selectivity. Taken together, these evidences provide insights into the selectivity mechanism of the complement regulator proteins encoded by the variola and vaccinia viruses to circumvent the complement immunity and exert their pathogenic action. These fundamental aspects are valuable for the development of novel vaccines and therapeutic strategies.

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Electrostatic Steering Accelerates C3d:CR2 Association

Cited by 9 publications

References 78 publications

Does Ionic Screening Lower Activation Barriers for Conformational Transitions in Proteins?

Does Ionic Screening Lower Activation Barriers for Conformational Transitions in Proteins?

Hydrodynamic Steering in Protein Association Revisited: Surprisingly Minuscule Effects of Considerable Torques

Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition

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