Browsing by Author "Zheng, Weihua"

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    Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1–42) and Amyloid Beta(1–40)
    (American Chemical Society, 2017) Zheng, Weihua; Tsai, Min-Yeh; Wolynes, Peter G.
    Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-β protein (1–42) and amyloid-β protein (1–40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of Aβ42 is more downhill, with a computed solubility that is about 10 times smaller than that of Aβ40. At a concentration of 40 μM, the clear free energy barrier between the pre-fibrillar tetramer form and the fibrillar pentamer in the Aβ40 aggregation landscape disappears for Aβ42, suggesting that the Aβ42 tetramer has a more diverse structural range. To further compare the landscapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on β-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that Aβ40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for Aβ42 relative to Aβ40, and greatly facilitate the conversion from pre-fibrillar trimers to fibrillar tetramers.
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    Resolving the NFκB Heterodimer Binding Paradox: Strain and Frustration Guide the Binding of Dimeric Transcription Factors
    (American Chemical Society, 2017) Potoyan, Davit A.; Bueno, Carlos; Zheng, Weihua; Komives, Elizabeth A.; Wolynes, Peter G.
    Many eukaryotic transcription factors function after forming oligomers. The choice of protein partners is a nonrandom event that has distinct functional consequences for gene regulation. In the present work we examine three dimers of transcription factors in the NFκB family: p50p50, p50p65, and p65p65. The NFκB dimers bind to a myriad of genomic sites and switch the targeted genes on or off with precision. The p65p50 heterodimer of NFκB is the strongest DNA binder, and its unbinding is controlled kinetically by molecular stripping from the DNA induced by IκB. In contrast, the homodimeric forms of NFκB, p50p50 and p65p65, bind DNA with significantly less affinity, which places the DNA residence of the homodimers under thermodynamic rather than kinetic control. It seems paradoxical that the heterodimer should bind more strongly than either of the symmetric homodimers since DNA is a nearly symmetric target. Using a variety of energy landscape analysis tools, here we uncover the features in the molecular architecture of NFκB dimers that are responsible for these drastically different binding free energies. We show that frustration in the heterodimer interface gives the heterodimer greater conformational plasticity, allowing the heterodimer to better accommodate the DNA. We also show how the elastic energy and mechanical strain in NFκB dimers can be found by extracting the principal components of the fluctuations in Cartesian coordinates as well as fluctuations in the space of physical contacts, which are sampled via simulations with a predictive energy landscape Hamiltonian. These energetic contributions determine the specific detailed mechanisms of binding and stripping for both homo- and heterodimers.