Rational Design of Angiotensin‐I‐Converting Enzyme Inhibitory Peptides by Integrating in silico Modeling and an in vitro Assay

Jing, Tao; Feng, Jian; Li, De; Liu, Jianping; He, Ge

doi:10.1002/cmdc.201300132

Cited by 21 publications

(8 citation statements)

References 83 publications

(33 reference statements)

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“…A genetic algorithm (GA) scheme modified from previous works was employed to optimize an AMP‐UAA population (Figure ).…”

Section: Methodsmentioning

confidence: 99%

Molecular design and genetic optimization of antimicrobial peptides containing unnatural amino acids against antibiotic‐resistant bacterial infections

2016

Biopolymers

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Antimicrobial peptides (AMPs) have been the focus of intense research towards the finding of a viable alternative to current small-molecule antibiotics, owing to their commonly observed and naturally occurring resistance against pathogens. However, natural peptides have many problems such as low bioavailability and high allergenicity that largely limit the clinical applications of AMPs. In the present study, an integrative protocol that combined chemoinformatics modeling, molecular dynamics simulations, and in vitro susceptibility test was described to design AMPs containing unnatural amino acids (AMP-UAAs). To fulfill this, a large panel of synthetic AMPs with determined activity was collected and used to perform quantitative structure-activity relationship (QSAR) modeling. The obtained QSAR predictors were then employed to direct genetic algorithm (GA)-based optimization of AMP-UAA population, to which a number of commercially available, structurally diverse unnatural amino acids were introduced during the optimization process. Subsequently, several designed AMP-UAAs were confirmed to have high antibacterial potency against two antibiotic-resistant strains, i.e. multidrug-resistant Pseudomonas aeruginosa (MDRPA) and methicillin-resistant Staphylococcus aureus (MRSA), with minimum inhibitory concentration (MIC) < 10 μg/ml. Structural dynamics characterizations revealed that the most potent AMP-UAA peptide is an amphipathic helix that can spontaneously embed into an artificial lipid bilayer and exhibits a strong destructuring tendency associated with the embedding process. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 746-756, 2016.

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“…A genetic algorithm (GA) scheme modified from previous works was employed to optimize an AMP‐UAA population (Figure ).…”

Section: Methodsmentioning

confidence: 99%

Molecular design and genetic optimization of antimicrobial peptides containing unnatural amino acids against antibiotic‐resistant bacterial infections

2016

Biopolymers

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“…A modified version of genetic algorithm was used to evolve a peptide population with improved potency to target YAP WW1 domain. The evaluation procedure is described as follows: The initial population consisted of 180 peptides that were randomly generated from the core ten‐residue sequence of Smad peptide with only one or two residue mutations.…”

Section: Methodsmentioning

confidence: 99%

Rational design of YAP WW1 domain‐binding peptides to target TGFβ/BMP/Smad–YAP interaction in heterotopic ossification

Dong

Liu

Zhang

et al. 2015

Journal of Peptide Science

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The transforming growth factor-β/bone morphogenic protein/Smad signaling pathway has been raised as a new and promising therapeutic target of heterotopic ossification, which is mediated by recruitment of transcription coactivator Yes-associated protein (YAP) to Smad. Here, we described a successful integration of computational modeling and experimental assay to rationally design novel peptide aptamers to disrupt YAP-Smad interaction by targeting YAP WW1 domain. In the protocol, a computational genetic evolution strategy was used to improve a population of potential YAP WW1-binding peptides generated from the YAP-recognition site in Smad protein, from which several promising peptides were selected and their affinities toward YAP WW1 domain were determined using binding assay. In addition, a high-activity peptide was further optimized based on its complex structure with YAP WW1 domain to derive a number of derivative peptides with higher binding potency to the domain. We also found that a strong YAP WW1 binder should have a negatively charged N-terminus, a positively charged C-terminus and a nonpolar core to match the electrostatic distribution pattern in peptide-binding pocket of YAP WW1 domain, which may also form additional nonbonded interactions such as hydrogen bond, salt bridge and π-π stacking to confer stability and specificity for the domain-peptide recognition.

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“…A peptide evolution scheme described by Jing et al 11. was used here to optimize a peptide population for high affinity binding to WW2 domain.…”

Section: Methodsmentioning

confidence: 99%

Targeting Yes‐associated Protein with Evolved Peptide Aptamers to Disrupt TGF‐β Signaling Pathway: Therapeutic Implication for Bone Tumor

Dong

2015

Molecular Informatics

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The binding of transcription coactivator Yes-associated protein (YAP) to Smad transcription factors is an important event in activating transforming growth factor-β (TGF-β) signaling pathway, which is involved in the tumorigenicity and metastasis of bone tumor. Design of peptide aptamers to disrupt YAPSmad interaction has been established as a promising approach for bone tumor therapy. Here, an evolution strategy was used to optimize Smad-derived peptides for high potency binding to YAP WW2 domain, resulting in an improved peptide population, from which those high-scoring candidates were characterized rigorously using molecular dynamics (MD) simulations and interaction free energy calculations. With the computational protocol we were able to generate a number of potential domain binders, which were then substantiated by using fluorescence spectroscopy assay. Subsequently, the complex structure of YAP WW2 domain with a high-affinity peptide was modeled and examined in detail, which was then used to guide structure-based peptide optimization to obtain several strong domain binders. Structural and energetic analysis revealed that electrostatic complementarity is primarily responsible for domainpeptide recognition, while other nonbonded interactions such as hydrogen bonding and salt bridges can contribute significantly to the recognition specificity.

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Rational Design of Angiotensin‐I‐Converting Enzyme Inhibitory Peptides by Integrating in silico Modeling and an in vitro Assay

Cited by 21 publications

References 83 publications

Molecular design and genetic optimization of antimicrobial peptides containing unnatural amino acids against antibiotic‐resistant bacterial infections

Molecular design and genetic optimization of antimicrobial peptides containing unnatural amino acids against antibiotic‐resistant bacterial infections

Rational design of YAP WW1 domain‐binding peptides to target TGFβ/BMP/Smad–YAP interaction in heterotopic ossification

Targeting Yes‐associated Protein with Evolved Peptide Aptamers to Disrupt TGF‐β Signaling Pathway: Therapeutic Implication for Bone Tumor

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