How Do Mutations and Allosteric Inhibitors Modulate Caspase-7 Activity? A Molecular Dynamics Study

Bingol E. N., Serçinoğlu O., Özbek Sarıca P.

Journal Of Biomolecular Structure & Dynamics, cilt.37, sa.13, ss.3456-3466, 2019 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 37 Sayı: 13
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1080/07391102.2018.1517611
  • Dergi Adı: Journal Of Biomolecular Structure & Dynamics
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.3456-3466
  • Anahtar Kelimeler: caspase-7, collective motions, global dynamics, amino acid interaction energies, molecular dynamics simulations, GENERAL FORCE-FIELD, STRUCTURAL-CHANGES, CRYSTAL-STRUCTURE, PROTEIN, CHARMM, NETWORK, LOOP, AUTOMATION, ACTIVATION, MECHANISMS
  • Marmara Üniversitesi Adresli: Evet

Özet

Caspases are members of a highly regulated aspartate-cysteine protease family which have important roles in apoptosis. Pharmaceutical studies focused on these molecules since they are involved in diseases such as cancer and neurodegenerative disorders. A small molecule which binds to the dimeric interface away from the binding site induces a conformational change that resembles the pro-caspase form of the molecule by shifting loop positions. The fluctuation mechanisms caused by mutations or binding of a ligand can explain the key mechanism for the function of that molecule. In this study, we performed molecular dynamics simulations on wild-type and mutated structures (C290N, R187M, Y223A, G188L and G188P) as well as allosterically inhibited structure (DICA-bound caspase-7) to observe the effects of the single mutations on intrinsic dynamics. The results show that previously known changes in …