Structure based peptide design, molecular dynamics and MM-PBSA studies for targeting C terminal dimerization of NFAT5 DNA binding domain

Timucin A. C.

JOURNAL OF MOLECULAR GRAPHICS & MODELLING, cilt.103, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 103
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.jmgm.2020.107804
  • Dergi Adı: JOURNAL OF MOLECULAR GRAPHICS & MODELLING
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Applied Science & Technology Source, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, Chimica, Compendex, Computer & Applied Sciences, EMBASE, INSPEC, MEDLINE
  • Anahtar Kelimeler: Cell penetrating peptide, Dimerization, NFAT5, Peptide, Relative binding free energy, STRUCTURE-BASED PREDICTION, CELL-PENETRATING PEPTIDES, NOVO STRUCTURE PREDICTION, FREE-ENERGY CALCULATIONS, WEB SERVER, OSMOTIC-STRESS, PEP-FOLD, PROTEIN, TRANSCRIPTION, EXPRESSION
  • Acıbadem Mehmet Ali Aydınlar Üniversitesi Adresli: Hayır

Özet

NFAT5 as a transcription factor with an established role in osmotic stress response, has also been revealed to be active under numerous settings, including pathological conditions such as diabetic microvascular complications, chronic arthritis and cancer. Despite these links, current strategies for downregulating NFAT5 activity only relies on indirect modulators, not directly targeting NFAT5, itself. With this study, through using a computational approach, an original peptide was explored to directly target C terminal dimerization of NFAT5 RHR, located in its DNA binding domain. At first, homodimeric NFAT5 RHR bound to its consensus DNA was used for prediction of a preliminary peptide sequence. Possible amino acid replacements for this preliminary peptide were predicted for optimization, which was followed by addition of a cell penetrating peptide sequence. These attempts yielded a small peptide library, which was further investigated for peptide affinities towards C terminal of NFAT5 RHR through molecular docking, 50 ns and 250 ns molecular dynamics simulations, followed by estimation of MMPBSA based relative binding free energies. Results indicated that after receiving mutations on the preliminary peptide sequence for optimization, a unique peptide could target C terminal dimerization region of NFAT5 RHR through using its cell penetrating peptide sequence. In conclusion, this is the first study presenting computational evidence on identification of a novel peptide capable of directly targeting NFAT5 dimerization. Besides, future implications of these observations were also discussed in terms of methodology and possible applications.