Identification and molecular modeling of novel endogenous activator proteins of Sirt-1: an in silico study

Sirt-1 is one of the most extensively studied mammalian Sirtuins that deacetylates histones and several non-histone proteins critical to cellular homeostasis. As a key sensor of cellular metabolism, it is regulated at multiple levels including transcriptional and post translational levels. As an allosteric enzyme, its activity is also modulated by ligands and certain endogenous proteins. The present study is an in silico approach to identify novel Sirt-1 binding proteins. Bioinformatic search for similarity in sequence, structure, and topology of binding region to Lamin-A, a known activator of Sirt-1, identified three proteins viz. Epididymis secretory sperm binding protein (ESSBP), xylosyltransferase 1 (XT-1), and Adenylyl cyclase 9 (ADCY-9). Molecular docking studies revealed binding of ESSBP and ADCY-9 to the N-terminal region of Sirt-1 while XT-1 docks at both N-terminal and C-terminal region of Sirt-1 with Z-Dock score better than Lamin-A; XT-1 and ADCY-9 showed better Z-Rank score as well. MD simulation studies for extended time followed by MM-PBSA analysis showed that the Sirt-1-protein complexes were stable with favourable binding energy and minimal change in RMSD relating to backbone structure and RMSF relating to residue fluctuations. Further, H-bond analysis showed only minimal changes in H bonding interactions. Docking of these proteins to Sirt-1 through interaction with several residues particularly to its N-terminal region spanning 1-243 residues, in a manner similar to the docking of the activator Lamin-A and different from the inhibitor DLBC-1 binding site, suggests that these proteins may also positively modulate Sirt-1 activity. Further experimental data would be required to validate the computational prediction and to understand its physiological role.Communicated by Ramaswamy H. Sarma.