p53 is a tumor suppressor protein that maintains genome stability, but its Δ133p53β and Δ160p53β isoforms promote breast cancer cell invasion. The sequence truncations in the p53 core domain raise key questions related to their physicochemical properties, including structural stabilities, interaction mechanisms, and DNA‐binding abilities. Herein, we investigated the conformational dynamics of Δ133p53β and Δ160p53β with and without binding to p53‐specific DNA by using molecular dynamics simulations. We observed that the core domains of the 2 truncated isoforms are much less stable than wild‐type (wt) p53β, and the increased solvent exposure of their aggregation‐triggering segment indicates their higher aggregation propensities than wt p53. We also found that Δ133p53β stability is modulable by peptide or DNA interactions. Adding a p53 peptide (derived from truncated p53 sequence 107–129) may help stabilize Δ133p53. Most importantly, our simulations of p53 isomer‐DNA complexes indicate that Δ133p53β dimer, but not Δ160p53β dimer, could form a stable complex with p53‐specific DNA, which is consistent with recent experiments. This study provides physicochemical insight into Δ133p53β, Δ133p53β‐DNA complexes, Δ133p53β's pathologic mechanism, and peptide‐based inhibitor design against p53‐related cancers.— Lei, J., Qi, R., Tang, Y., Wang, W., Wei, G., Nussinov, R., Ma, B. Conformational stability and dynamics of the cancer‐associated isoform Δ133p53β are modulated by p53 peptides and p53‐specific DNA. FASEB J. 33, 4225–4235 (2019). http://www.fasebj.org

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The D-glucose/D-galactose-binding protein (GGBP) from Escherichia coli is a substrate-binding protein (SBP) associated with sugar transport and chemotaxis. It is also a calcium-binding protein, which makes it unique in the SBP family. However, the functional importance of Ca 2+ binding is not fully understood. Here, the calcium-dependent properties of GGBP were explored by all-atom molecular dynamics simulations and Markov state model (MSM) analysis as well as single-molecule Forster resonance energy transfer (smFRET) measurements. In agreement with previous experimental studies, we observed the structure stabilization effect of Ca 2+ binding on the C-terminal domain of GGBP, especially the Ca 2+ -binding site. Interestingly, the MSMs of calcium-depleted GGBP and calcium-bound GGBP (GGBP/Ca 2+ ) demonstrate that Ca 2+ greatly stabilizes the open conformation, and smFRET measurements confirmed this result. Further analysis reveals that Ca 2+ binding disturbs the local hydrogen bonding interactions and the conformational dynamics of the hinge region, thereby weakening the long-range interdomain correlations to favor the open conformation. These results suggest an active regulatory role of Ca 2+ binding in GGBP, which finely tunes the conformational distribution. The work sheds new light on the study of calcium-binding proteins in prokaryotes.