Mª Dolores San Millán Vergé(**); Miguel Ibáñez Artica (***)
ABSTRACT The “Shell Money” of Oceania
II. MONEDAS-CONCHA EN MELANESIA
II.4. Mwali y Soulava, las monedas del Kula
My final specific aim is to utilize results from these molecular dynamics studies to develop new testable hypotheses. The h-core is evidently critical to the rigidity of cadherin domains and even the linker region. Our lab wants to conduct further studies on hydrophobic core residues by
evaluating the size and strength of h-core. Our lab wants to mutate critical h-core residues and measure the impact on thermal stability of N- and ECAD domains. We expect mutation of h-core residues to polar residues will result in destabilization of cadherin EC domains.
Our lab is also interested in studying the effects of Leu201/203 in EC1and EC2 stability of E- and NCAD respectively. Clearly, leucine has an important role in the ionic interactions that occur at the linker region. Our lab wants to mutate L201 and L203 to alanine to measure the impact of a smaller side chain on linker flexibility. Without the larger leucine side chain impeding R105:N102 interactions, we expect NCAD12 to exhibit R105:E107 and R105:E102 interactions. This will possibly destabilize the linker region to be similar to the linker region of ECAD12. We expect that thermal stability will decrease for NCAD12 L203A and ECAD12 L201A by further destabilizing the linker region.
Electrostatic interactions in the monomer are also a point of interest. The N-terminus:E89 salt-bridge interaction at EC1 of N- and ECAD is important to proper docking of W2 in the hydrophobic pocket and overall stability of the monomer structure. E89A mutation removes this salt-bridge, destabilizes the monomer, and drives dimerization to relieve energetic strain. W2 is never fully exposed during this process, and our lab believe the Aβ-sheet is stabilized by a series of salt-bridges involving the N-terminus:E89, D1:K30, and D1:K25 of ECAD and D1:R25 of NCAD interactions. Our lab wants to conduct mutation studies on R25 or K25 and K30. We expect depletion of salt-bridges at for the N-terminus to increase W2 exposure measurable by fluorescence and destabilize the monomer structure. This will change the monomer-dimer equilibrium and drive dimerization greater than just E89 mutation alone.
wants to utilize the monomer structures for molecular dynamics studies as a comparison tool for future dimer studies on N- and ECAD12. Importantly, we want to study all stages of monomer- dimer exchange in cadherins. Although the monomer structure is the starting state for monomer to dimer exchange, we also want to conduct MD studies on the intermediate X-dimer structure for ECAD and the strand-swapped dimer structures for N- and ECAD. Evaluation of each stage of monomer-dimer exchange will give us insight on the atomic changes and interactions that occur during strand-swapping in cadherins. MD studies for all three of these dimer structures have been started but are currently ongoing.
We are also interested in studying dimer structures for electrostatic purposes. ECAD has higher surface charges than NCAD, and our lab wants to evaluate the impact of K14E/R14E mutations on dimer ECAD12 and NCAD12 respectively. We expect K14E to reduce dimerization by impeding X-dimer formation. Although the intermediate structure of NCAD is not known, we expect the addition of glutamate in NCAD to reduce dimerization. Although MD simulations were analyzed for monomeric cadherins, evaluation of surface charge impact is determinant on the dimer structure. However, our lab needs the monomer structure as a comparison took to future dimer studies so the monomeric mutations are necessary and useful for future work. We have started MD simulations for NCAD R14E dimer, NCAD R14E X-enabled Dimer, ECAD K14E dimer, and ECAD K14E X-dimer. These experiments are ongoing.
Lastly, our lab wanted to measure the effects of proline mutation in N- and ECAD dimer. MD simulations were conducted on monomeric ECAD12 E16P and NCAD P16E. In order to determine the effects of proline on the monomer-dimer equilibrium of E- and NCAD our lab need to conduct MD studies on dimer. Monomeric studies are important for comparison, but the effect
of prolines is inconclusive until dimeric studies are performed.
In summation, molecular dynamics was a useful tool in accomplishing the goals for this thesis. I was able to complete the specific aims set for this thesis by: using a MD method to study N- and ECAD12 behavior, evaluating the intramolecular interactions that contribute to N- and ECAD12 domain stability, evaluating the effect of specific electrostatic interactions on the disposition of W2 in N- and ECAD12, evaluating the intramolecular interactions of proline and X-dimer mutations compared to WT N- and ECAD12, and, lastly, develop new testable hypotheses using molecular dynamics results.
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