Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2015 Oct;16(10):883-96.
doi: 10.1631/jzus.B1500106.

Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides

Hua Yu  1 , Mao-jun Wang  1 , Nan-xia Xuan  1 , Zhi-cai Shang  1 , Jun Wu  1
Affiliations

Molecular dynamics simulation of the interactions between EHD1 EH domain and multiple peptides

Hua Yu et al. J Zhejiang Univ Sci B. 2015 Oct.

Abstract

Objective: To provide essential information for peptide inhibitor design, the interactions of Eps15 homology domain of Eps15 homology domain-containing protein 1 (EHD1 EH domain) with three peptides containing NPF (asparagine-proline-phenylalanine), DPF (aspartic acid-proline-phenylalanine), and GPF (glycine-proline-phenylalanine) motifs were deciphered at the atomic level. The binding affinities and the underlying structure basis were investigated.

Methods: Molecular dynamics (MD) simulations were performed on EHD1 EH domain/peptide complexes for 60 ns using the GROMACS package. The binding free energies were calculated and decomposed by molecular mechanics/generalized Born surface area (MM/GBSA) method using the AMBER package. The alanine scanning was performed to evaluate the binding hot spot residues using FoldX software.

Results: The different binding affinities for the three peptides were affected dominantly by van der Waals interactions. Intermolecular hydrogen bonds provide the structural basis of contributions of van der Waals interactions of the flanking residues to the binding.

Conclusions: van der Waals interactions should be the main consideration when we design peptide inhibitors of EHD1 EH domain with high affinities. The ability to form intermolecular hydrogen bonds with protein residues can be used as the factor for choosing the flanking residues.

Keywords: Binding affinity; EHD1 EH domain; Inhibitor design; Molecular dynamics simulation; Peptide.

PubMed Disclaimer

Conflict of interest statement

Compliance with ethics guidelines: Hua YU, Mao-jun WANG, Nan-xia XUAN, Zhi-cai SHANG, and Jun WU declare that they have no conflict of interest.

This article does not contain any studies with human or animal subjects performed by any of the authors.

Figures

Fig. 1
Fig. 1
RMSD of the backbone atoms of the complex, protein, and peptide during the 60 ns production simulation Black: complex; Red: protein; Blue: peptide (Note: for interpretation of the references to color in this figure legend, the reader is referred to the web version of this article)
Fig. 2
Fig. 2
Structures of the complex 2KFFNPF and aligned structures of complexes 2KFFNPF, 2KFGDPF, and 2KFHGPF Structures of complex 2KFFNPF were viewed from the side (a) and the top (b) of the binding pocket. (c) The structure of peptide and protein residues numbered 68–102. The partition of the residues is consistent with the structure module in Fig. 3. (d) This picture was obtained by superimposing the residues on the protein interface numbered 68–102 of the three complexes. Protein and peptide were displayed in Surf and NewCartoon styles, respectively. The highlighted parts of the peptides represent Pro150 and Phe151
Fig. 3
Fig. 3
Secondary structure evolution of peptide and protein residues numbered 68–102 during 40–60 ns dynamics simulation Zero in the ordinate, as a chain separator, is the boundary of the protein and peptide residues. The upper part represents the peptide residues numbered 143–154, while the lower part represents the protein residues numbered 68–102
Fig. 4
Fig. 4
Hydrogen bond formed between Asn149/Asp149/Gly149 of the peptide and its protein partner during 40–60 ns production simulation Figure below shows the lifetime of the hydrogen bond. Red, the hydrogen bond is present at that time; white, not present. Zero in the ordinate is the hydrogen bond index and represents the hydrogen bond formed between Asn149 and Gly87 in 2KFFNPF, the hydrogen bond formed between Lys91 and Asp149 in 2KFGDPF, and the hydrogen bond formed between Lys73 and Gly149 in 2KFHGPF, respectively. Figure upper left shows the hydrogen bond. Protein is colored cyan; peptide, yellow. Residues forming hydrogen bonds are drawn in CPK mode. White represents hydrogen; blue, nitrogen; red, oxygen; magenta, carbon. The blue dotted line represents hydrogen bond. Figure upper right shows the distance distribution of donor-acceptor of hydrogen bond during 40–60 ns simulation
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ammann LP, Goodman SR. Cluster analysis for the impact of sickle cell disease on the human erythrocyte protein interactome. Exp Biol Med. 2009;234(6):703–711. doi: 10.3181/0806-RM-211. - DOI - PubMed
    1. Benmerah A, Gagnon J, Bègue B, et al. The tyrosine kinase substrate eps15 is constitutively associated with the plasma membrane adaptor AP-2. J Cell Biol. 1995;131(6):1831–1838. doi: 10.1083/jcb.131.6.1831. - DOI - PMC - PubMed
    1. Benmerah A, Lamaze C, Bègue B, et al. AP-2/Eps15 interaction is required for receptor-mediated endocytosis. J Cell Biol. 1998;140(5):1055–1062. doi: 10.1083/jcb.140.5.1055. - DOI - PMC - PubMed
    1. Berendsen HJC, Postma JPM, van Gunsteren WF, et al. Molecular dynamics with coupling to an external bath. J Chem Phys. 1984;81(8):3684–3690. doi: 10.1063/1.448118. - DOI
    1. Braun A, Pinyol R, Dahlhaus R, et al. EHD proteins associate with syndapin I and II and such interactions play a crucial role in endosomal recycling. Mol Biol Cell. 2005;16(8):3642–3658. doi: 10.1091/mbc.E05-01-0076. - DOI - PMC - PubMed

Publication types

MeSH terms