Allosteric regulation of protein activity pervades biology as the "second secret of life." We have been examining the allosteric regulation and mutant reactivation of the tumor suppressor protein p53. We have found that generalizing the definition of allosteric effector to include entire proteins and expanding the meaning of binding site to include the interface of a transcription factor with its DNA to be useful in understanding the modulation of protein activity. Here, we cast the variable regions of p53 isoforms as allosteric regulators of p53 interactions with its consensus DNA. We implemented molecular dynamics simulations and our lab's new techniques of molecular dynamics (MD) sectors and MD-Markov state models to investigate the effects of nine naturally occurring splice variant isoforms of p53. We find that all of the isoforms differ from wild type in their dynamic properties and how they interact with the DNA. We consider the implications of these findings on allostery and cancer treatment.

Allosteric signaling in proteins has been known for some half a century, yet how the signal traverses the protein remains an active area of research. Recently, the importance of electrostatics to achieve long-range signaling has become increasingly appreciated. Our laboratory has been working on developing network approaches to capture such interactions. In this study, we turn our attention to the well-studied allosteric model protein, PDZ. We study the allosteric dynamics on a perresidue basis in key constructs involving the PDZ domain, its allosteric effector, and its peptide ligand. We utilize molecular dynamics trajectories to create the networks for the constructs to explore the allosteric effect by plotting the heat kernel results onto axes defined by principal components. We introduce a new metric to quantitate the volume sampled by a residue in the latent space. We relate our findings to PDZ and the greater field of allostery.