1. Core Fragment 251ILTIITL257 of the Tumor Suppressor Protein p53 Enhances the Aggregation of Its I254R Mutant: A Prion-like Property
Jiangtao Leia, Ruxi Qia, Wenhui Xia, Buyong Mab*, Ruth Nussinovb, and Guanghong Weia*
aState Key Laboratory of Surface Physics and Department of Physics, Fudan University, Shanghai , China
bBasic Research Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, NCI, Frederick, Maryland 21702, USA
Introduction
3. The hybrid system displays similar inter-peptide interactions as the wild type system .
The tumor suppressor protein p53 loses its function in more than 50% of human malignant tumors. Recent studies have suggested that the p53 core domain has a greater tendency to form aggregates than the globular domain of the prion protein PrP1. However, the aggregation mechanism is unclear at atomic level. Here, using replica exchange molecular dynamics (REMD) simulations, we investigated the aggregations of wild type p53 core fragment (251ILTIITL257), its I254R mutant and their hybrid at 310 K.
Wild type
Mutant
Hybrid
Figure 3. Main chain−main chain and side chain−side chain contact probability maps.
Materials and Methods
Amino Acid Sequence: Ace-ILTIITL-Nme (wild type) and Ace-ILTRITL-Nme (mutant)
Simulation Method: REMD in NPT ensemble, 48 replicas,
P: 1 bar , T: K
Force Field: Amber99sb-ILDN
Systems:
Wild type : hexamer
Mutant : hexamer
Hybrid : wild type (trimer) + mutant (trimer)
Water Model: TIP3P
Packages: Gromacs , Amber12, VMD and PyMOL
4. The hybrid system has similar free energy landscape as the wild type.
Figure 4. Free energy landscape (in kcal/mol).
5. The wild type species has a higher propensity to form β-sheet with its mutant in the hybrid system.
Results
1. Wild type promotes the b-sheet formation of its I254R mutant.
Table 1. The β-sheet probability of WT-WT, WT-MT and MT-MT in the hybrid system.
Table 2. Binding energies (in kcal/mol).
Figure 1. Analysis of secondary structure.
Conclusions
We have investigated the aggregation of the core fragment 251ILTIITL257 of p53 protein, its I254R mutant, and their hybrid. Our simulations showed the hybrid system has similar b-sheet content and free energy landscape as the wild type. These results demonstrate that the wild type promotes the aggregation of its mutant, revealing a prion-like aggregation property.
2. The oligomeric structures of hybrid are similar to those of the wild type.
References
Figure 2. The b-sheet size distribution and the time evolution of connectivity length.
1, Rangel, L.P. et al. Prion. 8, 75–84 (2014)
2, Xu, J. et al. Nat. Chem. Biol. 7, 285–295 (2011)