Machine annealing‐guided navigation of antihypertensive food peptide selectivity between human <scp>ACE</scp> N‐ and C‐domains in structurally interacting diversity space

Mei, Li; Shang, Shuyong; Wang, Shaozhou; Ye, Haiyang; Zhou, Peng

doi:10.1002/jmr.3014

Cited by 14 publications

(1 citation statement)

References 69 publications

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“…The basis set superposition error (BSSE) was eliminated by using a counterpoise method (Boys & Bernardi, 1970). Peptide selectivity was also investigated based on the binding energy calculations (Mei et al, 2023;Shu et al, 2023).…”

Section: Preparation Of the Crystal Complex Structure Of Il-5rα Prote...mentioning

confidence: 99%

Molecular design and systematic optimization of a halogen‐bonding system between the asthma interleukin‐5 receptor and its cyclic peptide ligand

He,

Xu,

et al. 2023

Chem Biol Drug Des

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Human interleukin‐5 (IL‐5) functions as an important pro‐inflammatory factor by binding to its specific receptor, IL‐5Rα, which has been implicated in the pathogenesis of asthma. Previously, a disulfide‐bonded cyclic peptide AF17121 obtained from random library screening and sequence variation was found to competitively disrupt the cognate IL‐5Rα/IL‐5 interaction with moderate potency. In this study, the crystal complex of IL‐5Rα with AF17121 was investigated at structural and energetic levels. It is revealed that the side‐chain indole moiety of the AF17121 Trp5 residue is a potential site for a stem putative halogen bond (X‐bond) with IL‐5Rα, which is just located within the key 3EXXR6 motif region recognized specifically by IL‐5Rα. We systematically examined four halogen substitution types at five positions of the indole moiety; QM/MM calculations theoretically unraveled that only halogenations at 5 and 6 positions can form effective X‐bonds with the side‐chain hydroxyl oxygen of the IL‐5Rα Thr21 residue and the backbone carbonyl oxygen of Ala66 residue, respectively. Binding assays observed that I‐substitution at the 5 position and Br‐substitution at the 6 position can result in two potent halogenated peptides, [5I]AF17121 and [6Br]AF17121, which are improved by 1.6‐fold and 3.5‐fold relative to the native AF17121, respectively. 5I/6Br‐double substitution, resulting in [5I/6Br]AF17121, can further enhance the peptide affinity by 7.5‐fold. Structural analysis revealed that the X‐bond stemming from 6Br‐substitution is also involved in an orthogonal interaction system with a H‐bond; they share a common backbone carbonyl oxygen acceptor of IL‐5Rα Ala66 residue and exhibit a significant synergistic effect between them.

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Section: Preparation Of the Crystal Complex Structure Of Il-5rα Prote...mentioning

confidence: 99%

Molecular design and systematic optimization of a halogen‐bonding system between the asthma interleukin‐5 receptor and its cyclic peptide ligand

He,

Xu,

et al. 2023

Chem Biol Drug Des

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Targeting peptide‐mediated interaction between the N‐protein and P‐protein of human pediatric respiratory syncytial virus by molecular design of chemically stapled helical peptides

Yan

Zhang

et al. 2023

J Chinese Chemical Soc

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BackgroundHuman respiratory syncytial virus (hRSV) is a leading viral etiologic agent of pediatric lower respiratory infection in infants, young children, and immunocompromised elderly individuals.ObjectiveTargeting the intermolecular interaction between the viral nucleocapsid protein (N‐protein) and phosphoprotein (P‐protein) has been recognized as a promising therapeutic strategy against hRSV infection, which is a so‐called peptide‐mediated protein/protein interaction (PmPPI) by binding the short C‐terminal tail of P‐protein to the globular domain of N‐protein.MethodsThe PmPPI dynamics behavior and thermodynamics property were investigated systematically by integrating computational simulations and experimental assays.ResultsIt is revealed that the C‐terminal tail of P‐protein is intrinsically disordered in free state but would fold into a structured helix when binding to N‐protein, known as coupled folding‐upon‐binding, thus incurring a considerable entropy penalty upon the binding. Several flexible P‐peptide segments with different lengths were derived from the C‐terminus of P‐protein and then stapled chemically by using an all‐hydrocarbon bridge, which effectively constrained the peptide disordered conformation into an ordered helical form in free state, thus considerably improving their affinity to N‐protein by minimizing the unfavorable entropy penalty.ConclusionsElectrostatic contribution is primarily responsible for N/P complex stability, while other noncovalent factors such as hydrogen bond and aromatic stacking confer specificity to the complex recognition. The Phe241 residue at the C‐terminal end of P‐protein plays a crucial role that anchors the flexible C‐terminal tail of P‐protein to a druggable pocket on N‐protein surface.

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Molecular modeling and rational design of disulfide‐stapled self‐inhibitory peptides to target IL‐17A/IL‐17RA interaction

Huang

Zhou

Pan

et al. 2023

J of Molecular Recognition

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Interleukin‐17A (IL‐17A) is a pro‐inflammatory cytokine implicated in diverse autoimmune and inflammatory disorders such as psoriasis and Kawasaki disease. Mature IL‐17A is a homodimer that binds to the extracellular type‐III fibronectin D1:D2‐dual domain of its cognate IL‐17 receptor A (IL‐17RA). In this study, we systematically examined the structural basis, thermodynamics property, and dynamics behavior of IL‐17RA/IL‐17A interaction and computationally identified two continuous hotspot regions separately from different monomers of IL‐17A homodimer that contribute significantly to the interaction, namely I‐shaped and U‐shaped segments, thus rendered as a peptide‐mediated protein–protein interaction (PmPPI). Self‐inhibitory peptides (SIPs) are derived from the two segments to disrupt IL‐17RA/IL‐17A interaction by competitively rebinding to the IL‐17A‐binding pocket on IL‐17RA surface, which, however, only have a weak affinity and low specificity for IL‐17RA due to lack of the context support of intact IL‐17A protein, thus exhibiting a large flexibility and intrinsic disorder when splitting from the protein context and incurring a considerable entropy penalty when rebinding to IL‐17RA. The U‐shaped segment is further extended, mutated and stapled by a disulfide bridge across its two strands to obtain a number of double‐stranded cyclic SIPs, which are partially ordered and conformationally similar to their native status at IL‐17RA/IL‐17A complex interface. Experimental fluorescence polarization assays substantiate that the stapling can moderately or considerably improve the binding affinity of U‐shaped segment‐derived peptides by 2–5‐fold. In addition, computational structural modeling also reveals that the stapled peptides can bind in a similar mode with the native crystal conformation of U‐shaped segment in IL‐17RA pocket, where the disulfide bridge is out of the pocket for avoiding intervene of the peptide binding.

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Machine annealing‐guided navigation of antihypertensive food peptide selectivity between human ACE N‐ and C‐domains in structurally interacting diversity space

Cited by 14 publications

References 69 publications

Molecular design and systematic optimization of a halogen‐bonding system between the asthma interleukin‐5 receptor and its cyclic peptide ligand

Molecular design and systematic optimization of a halogen‐bonding system between the asthma interleukin‐5 receptor and its cyclic peptide ligand

Targeting peptide‐mediated interaction between the N‐protein and P‐protein of human pediatric respiratory syncytial virus by molecular design of chemically stapled helical peptides

Molecular modeling and rational design of disulfide‐stapled self‐inhibitory peptides to target IL‐17A/IL‐17RA interaction

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