(465a) Molecular Dynamics Simulations Uncovering the Key Stabilizing Interactions in the p53 Tetramerization Domain

The capacity of tumor suppressor protein p53 to function as a transcription factor depends on the formation of a tetrameric assembly. The TP53 gene is mutated in more than 50% of human cancers, and the majority of these missense mutations are thought to decrease the tumor suppressor activity of p53. Experiments investigating mutant peptides from the tetramerization domain indicated that most of the mutations found destabilize the specific tetramer structure of p53. Some mutants cannot form tetramers, and the peptides exist as unfolded monomers or as folded dimers at physiological concentrations and body temperature (reviewed in 1). Additionally, molecular dynamics simulations have been used to study mutant p53 and the effect specific mutations have on the stability of the tetramerization domain (2). Nevertheless, the key interactions and their corresponding role to stabilize the complex folding of the tetramerization domain still elude understanding. Here, we used a combination of computational and experimental methods to investigate principles of the stabilization of the tetramerization domain. Computational methods comprised an in-silico throughput screening tool with molecular modeling, molecular dynamics simulations, and structural and energy calculations. Our results comply with previous experimental findings on mutants destabilizing the tetramerization domain and provide fundamental insights into the destabilization process. Additionally, our studies provide in-detail structural and biophysical characterization of the key interactions between the different counterparts of the tetramer that contribute to the complex folding and stabilization of this domain.

1. Kamada et al. Biopolymers. 2016;106(4):598-612.
2. Rigoli et al. Int J Mol Sci. 2022;23(14):7960.