Electrostatic exploration of the C3d–FH4 interaction using a computational alanine scan

El-Assaad, Atlal; Kieslich, Chris A.; Gorham, Ronald D.; Morikis, Dimitrios

doi:10.1016/j.molimm.2011.05.007

Cited by 10 publications

(5 citation statements)

References 31 publications

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“…For our analysis we used the AESOP computational framework [27-31], which provides a platform for elucidating the role of electrostatics, and more specifically the role of ionizable amino acids, in protein association. This is accomplished using theoretical alanine scan or other mutagenesis, in which electrostatic properties are perturbed by systematically removing ionizable amino acids [27-31,48,49,51]. The effects of these perturbations are then quantified through the use of electrostatic similarity clustering and electrostatic free energies of association, to give insights into the contributions of ionizable amino acids in both recognition and binding [27,28,30,31,48,49,51].…”

Section: Methodsmentioning

confidence: 99%

“…This is accomplished using theoretical alanine scan or other mutagenesis, in which electrostatic properties are perturbed by systematically removing ionizable amino acids [27-31,48,49,51]. The effects of these perturbations are then quantified through the use of electrostatic similarity clustering and electrostatic free energies of association, to give insights into the contributions of ionizable amino acids in both recognition and binding [27,28,30,31,48,49,51]. Since electrostatics is also known to be an important aspect of protein dynamics and evolution, AESOP also has utilities for analyzing the electrostatics of molecular dynamics trajectories [28] and homologous proteins/protein domains [31,47,50].…”

Section: Methodsmentioning

confidence: 99%

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Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties

et al. 2012

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BackgroundThe V3 loop of the glycoprotein gp120 of HIV-1 plays an important role in viral entry into cells by utilizing as coreceptor CCR5 or CXCR4, and is implicated in the phenotypic tropisms of HIV viruses. It has been hypothesized that the interaction between the V3 loop and CCR5 or CXCR4 is mediated by electrostatics. We have performed hierarchical clustering analysis of the spatial distributions of electrostatic potentials and charges of V3 loop structures containing consensus sequences of HIV-1 subtypes.ResultsAlthough the majority of consensus sequences have a net charge of +3, the spatial distribution of their electrostatic potentials and charges may be a discriminating factor for binding and infectivity. This is demonstrated by the formation of several small subclusters, within major clusters, which indicates common origin but distinct spatial details of electrostatic properties. Some of this information may be present, in a coarse manner, in clustering of sequences, but the spatial details are largely lost. We show the effect of ionic strength on clustering of electrostatic potentials, information that is not present in clustering of charges or sequences. We also make correlations between clustering of electrostatic potentials and net charge, coreceptor selectivity, global prevalence, and geographic distribution. Finally, we interpret coreceptor selectivity based on the N6X7T8|S8X9 sequence glycosylation motif, the specific positive charge location according to the 11/24/25 rule, and the overall charge and electrostatic potential distribution.ConclusionsWe propose that in addition to the sequence and the net charge of the V3 loop of each subtype, the spatial distributions of electrostatic potentials and charges may also be important factors for receptor recognition and binding and subsequent viral entry into cells. This implies that the overall electrostatic potential is responsible for long-range recognition of the V3 loop with coreceptors CCR5/CXCR4, whereas the charge distribution contributes to the specific short-range interactions responsible for the formation of the bound complex. We also propose a scheme for coreceptor selectivity based on the sequence glycosylation motif, the 11/24/25 rule, and net charge.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties

et al. 2012

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“…Several diseases were revealed through the effect of charged amino acids 20 . Similar diseases include the eye disease known as Age-related Macular Degeneration (AMD) 21 , the kidney disease known as atypical Hemolytic Uremic Syndrome (aHUS), the Dense Deposit Disease (DDD), also known as membranoproliferative glomerulonephritis 22 , and immune system disorder (over-activity or under-activity) 23 . The electrostatic type of interactions was shown in complexes like C3d–CR2 24 – 27 and C3d–EfbC/Ehp association 26 – 29 , and in interactions with viral proteins VCP/SPICE 30 , 31 and Kaposica 32 .…”

Section: Methodsmentioning

confidence: 99%

Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome

El-Assaad

Dawy

Khalil

et al. 2021

Sci Rep

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Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.

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“…When relative binding was measured using SPR, the relative binding strength of SPICE for HuC3b was ∼130fold higher than for VCP (Yadav et al, 2008), and relative binding strength of VCP for BoC3b was ∼2.6 fold higher than for SPICE (Yadav et al, 2012). Several computational studies have revealed a key role of the electrostatics in the binding of CCP modules to the complement receptors, (Sfyroera et al, 2005;Zhang and Morikis, 2006;Yadav et al, 2008;Liszewski et al, 2009;El-Assaad et al, 2011;Kieslich et al, 2011c;Kieslich and Morikis, 2012;Yadav et al, 2012;Harrison et al, 2015;Mohan et al, 2015;Harrison et al, 2020), demonstrating that the diverse electrostatic properties of CCP modules mediate different specificities toward the complement proteins. Kieslich and Morikis (Kieslich and Morikis, 2012) have examined the effect of electrostatic interactions at the level of the complement C3 fragment C3d and its complement receptor 2 (CR2), whose formation constitutes the link between innate and adaptive immunity, proposing that the C3d-CR2 electrostatic specificity is critical in the onset of adaptive immunity.…”

Section: Introductionmentioning

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 exploration of the C3d–FH4 interaction using a computational alanine scan

Cited by 10 publications

References 31 publications

Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties

Clustering of HIV-1 Subtypes Based on gp120 V3 Loop electrostatic properties

Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome

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

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