Conformational dynamics of p53 and its two isoforms studied by molecular dynamics simulations Jiangtao Leia, Ruxi Qia, Buyong Mab*, Ruth Nussinovb, and Guanghong Weia* aState Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai 200433, China bBasic Research Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, NCI, Frederick, Maryland 21702, USA Introduction Materials and Methods As a tumour suppressor, p53 protein can express 12 different physiological isoforms that can regulate p53 transcriptional activity in different cancer cell. In these p53 isoforms, ∆133p53β is interesting because it can promote breast cancer cell invasion, improve cancer stem cell potential and regulate colorectal cancer cell apoptosis. Here, we investigate that the conformational dynamics of p53 and its two isoforms (∆133p53β and ∆160p53β) to understand they functions by molecular dynamics simulations. The results show that the deletion of N-terminal domains leads to structural instability of p53 isoforms, the p53 target DNA can stabilize structure of ∆133p53β similar to p53. Finally, the designing peptide (107 to 129) that is from wild type p53 can rescue the unstable structure of ∆133p53β efficiently. Simulation Methods : MD in NPT ensemble at 310k Force Field : charmm27 Water Model : TIP3P Three systems : 1. System i: 94-341p53β, 133p53β and 160p53β 2. System ii: 133p53β (dimer) + DNA 160p53β (dimer) + DNA 3. System iii: 133p53β + peptides Software : Gromacs - 4.5.3 , VMD and PyMOL Results 1. More deletion of the N-terminal domains more destabilizes the structure of p53 isoforms. Figure 2. Structural superimposition of core domain of p53 and its two isoforms. Figure 3. Covariance matrix analyses . Salt bridges 132-271 132-298 158-258 164-271 273-298 282-286 94-341p53β 94.6% 87.8% 99.7% 99.5% 99.4% 100.0% 133p53β - 99.7 97.5% 15.0% 160p53β 96.8% 2.4% Table 1. Salt bridges in p53 core domain Figure 1. The structural stability analyses. 2. When interacting with the p53 target DNA, ∆133p53β becomes more stable, whereas ∆160p53β is still unstable. Figure 4. The structural stability analyses. Figure 5. Structural superimposition Figure 6. Contact probability between each amino acid residue and DNA 3. The peptide (107 to 129) can stabilize structure of ∆133p53β. Figure 9. Covariance matrix analyses . Figure 7. The initial structures Figure 8. The structural stability analyses. Conclusions The stability: 94-341p53β > ∆133p53β > ∆160p53β. It indicates that more deletion of the N-terminal domains will more destabilize the structure of p53 isoforms. The structure of ∆133p53β can become more stable with the presence of DNA. The peptide (107 to 129) can rescue the unstable structure of ∆133p53β and ensure that ∆133p53β have the residue-residue association pattern similar to p53.