Protein–peptide docking: opportunities and challenges

Ciemny, Maciej Pawel; Kurciński, Mateusz; Kamel, Karol; Koliński, Andrzej; Alam, Nawsad; Schueler‐Furman, Ora; Kmiecik, Sebastian

doi:10.1016/j.drudis.2018.05.006

Cited by 228 publications

(226 citation statements)

References 68 publications

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“…Fmoc-AAs can be bioligands of diverse proteins. Targeting protein-peptide interactions is an attractive approach for state-of-the-art drug discovery and design (Ciemny et al, 2018). Efficient geometry and binding-mode descriptors are crucial for understanding protein-ligand interactions.…”

Section: A First Look At Fmoc-based Interactions In Biocomplexesmentioning

confidence: 99%

Synthesis, experimental andin silicostudies ofN-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Bojarska

Remko²,

Madura

et al. 2020

Acta Crystallogr C Struct Chem

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Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc–tyrosine or Fmoc–phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc‐protected amino acid, namely, 2‐{[(9H‐fluoren‐9‐ylmethoxy)carbonyl](methyl)amino}‐3‐{4‐[(2‐hydroxypropan‐2‐yl)oxy]phenyl}propanoic acid or N‐fluorenylmethoxycarbonyl‐O‐tert‐butyl‐N‐methyltyrosine, Fmoc‐N‐Me‐Tyr(t‐Bu)‐OH, C29H31NO5, was successfully synthesized and the structure of its unsolvated form was determined by single‐crystal X‐ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N‐Fmoc‐phenylalanine [Draper et al. (2015). CrystEngComm, 42, 8047–8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H…H, C…H/H…C and O…H/H…O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen‐bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C—H…O, C—H…π, (fluorenyl)C—H…Cl(I), C—Br…π(fluorenyl) and C—I…π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long‐Range Synthon Aufbau Modules, further supported by energy‐framework calculations, are discussed. Furthermore, the relevance of Fmoc‐based supramolecular hydrogen‐bonding patterns in biocomplexes are emphasized, for the first time.

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Section: A First Look At Fmoc-based Interactions In Biocomplexesmentioning

confidence: 99%

Synthesis, experimental andin silicostudies ofN-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Bojarska

Remko²,

Madura

et al. 2020

Acta Crystallogr C Struct Chem

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“…In addition, the application of restraints also proved to be very effective in preserving the cyclic conformation of the docked peptide (cyclic antagonist PMX53 docked to the C5a1 receptor, ODB ID: 6C1R). One of the major challenges of the methods for protein-peptide docking is the scoring of a large set of models generated during predictions [6] because the score value does not always correlate with model quality. For optimal selection of the final 10 top-scored models resulting from STAGE 3 of the modeling protocol we used a two-step hierarchical approach.…”

Section: Figurementioning

confidence: 99%

“…Due to the large interest in peptide therapeutics, many new protein-peptide docking techniques have been developed recently [6]. These may be divided into three categories: template-based docking, local docking and global docking tools [6]. Template-based docking uses structural data from analogous protein-peptide complexes.…”

Section: Introductionmentioning

confidence: 99%

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Badaczewska-Dawid

Kmiecik

Koliński

2020

Preprint

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The structural description of peptide ligands bound to G protein-coupled receptors (GPCRs) is important for the discovery of new drugs and deeper understanding of the molecular mechanisms of life. Here we describe a three-stage protocol for the molecular docking of peptides to GPCRs using a set of different programs: (1) CABS-dock for docking fully flexible peptides; (2) PD2 method for the reconstruction of atomistic structures from C-alpha traces provided by CABS-dock and (3) Rosetta FlexPepDock for the refinement of protein-peptide complex structures and model scoring. We evaluated the proposed protocol on the set of 7 different GPCR-peptide complexes (including one containing a cyclic peptide) for which crystallographic structures are available. We show that CABS-dock produces high resolution models in the sets of top-scored models. These sets of models, after reconstruction to all-atom representation, can be further improved by Rosetta high-resolution refinement and/or minimization, leading in most of the cases to sub-Angstrom accuracy in terms of interface RMSD measure.

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“…Peptides with a special sequence interact with proteins , cells , and DNA . When a peptide with a molecular recognition function combines with an information transfer molecule, the series of the molecule acts as a powerful probe and can be a tool for the sensing of a specific target .…”

Section: Introductionmentioning

confidence: 99%

Electrochemical Sensing of Ovalbumin Based on the Interaction between Lysozyme Origin/Tyrosine‐rich Peptides Modified on Magnetic Beads and Oligothreonine/Ovalbumin‐origin Peptide

et al. 2019

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We developed a highly sensitive electrochemical system for the sensing of ovalbumin (OVA). Lysozyme origin/tyrosine‐rich peptides (RNRCKGTDVQAWY4C) were immobilized on magnetic beads, and the competitive reaction between OVA and oligothreonine/OVA origin peptide probe (T8VLLPDEVSG) could then be measured. In a previous study, the detection of OVA at the 10−13 M level was achieved using RNRCKGTDVQAWY4C‐modified beads via a cross‐linker. To improve the sensitivity to OVA, this system uses T8VLLPDEVSG peptide probe to measure the interaction to RNRCKGTDVQAWY4C immobilized on magnetic beads. The peak of Y4C actually was an electron‐transfer peptide, which represented the oxidation of a phenolic hydroxyl group. First, we confirmed that the oxidation response of Y4C was increased based on an improvement in the electron transfer accessibility by oligothreonine. Next, T8VLLPDEVSG peptide probe was used for the electrochemical sensing of OVA in solutions that contained consistent amounts of RNRCKGTDVQAWY4C on magnetic beads. As a result, the peak current decreased as the concentration of OVA increased. The sensitivity to OVA was improved compared with the use of only RNRCKGTDVQAWY4C on magnetic beads. The OVA detection level was 10−14 M, which approximates the results from antibody‐antigen reactions. Consequently, the proposed system is a powerful new concept in protein sensing.

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Protein–peptide docking: opportunities and challenges

Cited by 228 publications

References 68 publications

Synthesis, experimental andin silicostudies ofN-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Synthesis, experimental andin silicostudies ofN-fluorenylmethoxycarbonyl-O-tert-butyl-N-methyltyrosine, coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Docking of peptides to GPCRs using a combination of CABS-dock with FlexPepDock refinement

Electrochemical Sensing of Ovalbumin Based on the Interaction between Lysozyme Origin/Tyrosine‐rich Peptides Modified on Magnetic Beads and Oligothreonine/Ovalbumin‐origin Peptide

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