Pawan Kumar Raghav, Yogesh Kumar Verma, Gurudutta U Gangenahalli
Stem Cell and Gene Therapy Research Laboratory, Institute of Nuclear Medicine and Allied Sciences (INMAS), Lucknow Road, Timarpur, Delhi-110054, India.
Besides four Bcl-2 homology (BH1, BH2, BH3 and BH4) domains, the flexible loop domain (FLD) of Bcl-2 is also important in regulating apoptosis. The FLD regulates apoptosis by interacting with JNK-1, PKC, PP2A phosphatase caspase-3, MAPKinase, Ubiquitin, PS1 and FKBP38 proteins. In addition, mutations in FLD at ASP34, Thr56, Thr69, Ser70, Thr74 and Ser87 disrupt Bcl-2 anti-apoptotic function. Therefore to predict the FLD behavior, it is essential to elucidate its folding and consequent effect on the overall Bcl-2 protein through simulations. We have predicted flexibility and stability behavior of FLD by Molecular Dynamics (MD) simulations. The simulated improved quality average structure (ID: PM0076467) and ensemble of 23 structures (ID: PM0077081-PM0077103) were submitted in protein model database (PMDB). The optimized FLD was used to predict the collective motions and essential subspace relevant for Bcl-2 protein functions which revealed that conformational changes in FLD likely affect BH3 cleft. These results provide a possible reason for difference between BH3 cleft of 1GJH (NMR) and 2XA0 (X-ray) models. Our study would facilitate understanding of the structural basis of Bcl-2 anti-apoptotic activity regulation upon binding with other proteins through FLD. Read More …