Consensus protein design

Porebski, Benjamin T.; Buckle, Ashley M.

doi:10.1093/protein/gzw015

Cited by 182 publications

(171 citation statements)

References 109 publications

(194 reference statements)

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“…A semi-rational design employing consensus peptide design has proven to be a popular and successful strategy in designing peptides with enhanced stability with regard to their physicochemical properties 10. The consensus design is based on the use of evolutionary information derived from homologous peptide sequences 11.…”

Section: Introductionmentioning

confidence: 99%

Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides

Almaaytah¹,

Ajingi²,

Abualhaijaa³

et al. 2016

IDR

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The rise of multidrug-resistant bacteria is causing a serious threat to the world’s human population. Recent reports have identified bacterial strains displaying pan drug resistance against antibiotics and generating fears among medical health specialists that humanity is on the dawn of entering a post-antibiotics era. Global research is currently focused on expanding the lifetime of current antibiotics and the development of new antimicrobial agents to tackle the problem of antimicrobial resistance. In the present study, we designed a novel consensus peptide named “Pepcon” through peptide consensus sequence determination among members of a highly homologous group of scorpion antimicrobial peptides. Members of this group were found to possess moderate antimicrobial activity with significant toxicity against mammalian cells. The aim of our design method was to generate a novel peptide with an enhanced antimicrobial potency and selectivity against microbial rather than mammalian cells. The results of our study revealed that the consensus peptide displayed potent antibacterial activities against a broad range of Gram-positive and Gram-negative bacteria. Our membrane permeation studies displayed that the peptide efficiently induced membrane damage and consequently led to cell death through the process of cell lysis. The microbial DNA binding assay of the peptide was found to be very weak suggesting that the peptide is not targeting the microbial DNA. Pepcon induced minimal cytotoxicity at the antimicrobial concentrations as the hemolytic activity was found to be zero at the minimal inhibitory concentrations (MICs). The results of our study demonstrate that the consensus peptide design strategy is efficient in generating peptides.

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Section: Introductionmentioning

confidence: 99%

Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides

Almaaytah¹,

Ajingi²,

Abualhaijaa³

et al. 2016

IDR

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“…Ankyrin repeat proteins consist of repeats of a 33-residue helix-loop-helix-loop motif 94,95 . The development of highly stable variants of repeat proteins was accomplished using the consensus design approach, 96 by which homologous sequences were compared to determine the optimal residues at each position in the repeat unit 97–98 . To improve the thermostability of designed ankyrin repeats, Caflisch and co-workers combined equilibrium unfolding experiments and high temperature MD simulations to investigate the effects of the number of repeats on stability 99 .…”

Section: Modulating Protein Stabilitymentioning

confidence: 99%

Insights from molecular dynamics simulations for computational protein design

Childers

Daggett

2017

Mol. Syst. Des. Eng.

173

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A grand challenge in the field of structural biology is to design and engineer proteins that exhibit targeted functions. Although much success on this front has been achieved, design success rates remain low, an ever-present reminder of our limited understanding of the relationship between amino acid sequences and the structures they adopt. In addition to experimental techniques and rational design strategies, computational methods have been employed to aid in the design and engineering of proteins. Molecular dynamics (MD) is one such method that simulates the motions of proteins according to classical dynamics. Here, we review how insights into protein dynamics derived from MD simulations have influenced the design of proteins. One of the greatest strengths of MD is its capacity to reveal information beyond what is available in the static structures deposited in the Protein Data Bank. In this regard simulations can be used to directly guide protein design by providing atomistic details of the dynamic molecular interactions contributing to protein stability and function. MD simulations can also be used as a virtual screening tool to rank, select, identify, and assess potential designs. MD is uniquely poised to inform protein design efforts where the application requires realistic models of protein dynamics and atomic level descriptions of the relationship between dynamics and function. Here, we review cases where MD simulations was used to modulate protein stability and protein function by providing information regarding the conformation(s), conformational transitions, interactions, and dynamics that govern stability and function. In addition, we discuss cases where conformations from protein folding/unfolding simulations have been exploited for protein design, yielding novel outcomes that could not be obtained from static structures.

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“…Immobilization of enzymes on heterogeneous catalysts [104][105][106] and preparation of cross-linked enzyme aggregates [107] are well-developed methods to improve the activity and stability of enzymes at extreme conditions, and to facilitate enzyme recycling. In addition, engineering enzymes by rational design [108,109] and directed evolution [110] are alternative ways to obtain enzyme mutants with improved properties and new functions. The combination of these techniques will enable integration of chemocatalysis and biocatalysis for advanced synthesis.…”

Section: Future Prospects and Conclusionmentioning

confidence: 99%

Tandem Reactions Combining Biocatalysts and Chemical Catalysts for Asymmetric Synthesis

Wang

Zhao

2016

Catalysts

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Abstract:The application of biocatalysts in the synthesis of fine chemicals and medicinal compounds has grown significantly in recent years. Particularly, there is a growing interest in the development of one-pot tandem catalytic systems combining the reactivity of a chemical catalyst with the selectivity engendered by the active site of an enzyme. Such tandem catalytic systems can achieve levels of chemo-, regio-, and stereo-selectivities that are unattainable with a small molecule catalyst. In addition, artificial metalloenzymes widen the range of reactivities and catalyzed reactions that are potentially employable. This review highlights some of the recent examples in the past three years that combined transition metal catalysis with enzymatic catalysis. This field is still in its infancy. However, with recent advances in protein engineering, catalyst synthesis, artificial metalloenzymes and supramolecular assembly, there is great potential to develop more sophisticated tandem chemoenzymatic processes for the synthesis of structurally complex chemicals.

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Consensus protein design

Cited by 182 publications

References 109 publications

Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides

Peptide consensus sequence determination for the enhancement of the antimicrobial activity and selectivity of antimicrobial peptides

Insights from molecular dynamics simulations for computational protein design

Tandem Reactions Combining Biocatalysts and Chemical Catalysts for Asymmetric Synthesis

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