Vigo-Pelfrey C, Lee D, Keim P, Lieberburg I, Schenk DB (1993) J Neurochem 61:1965–1968 Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, Younkin SG (1992) Science 258:126–129 Roher AE, Chaney MO, Kuo YM, Webster SD, Stine WB, Haverkamp LJ, Woods AS, Cotter RJ, Tuohy JM, Krafft GA, Bonnell BS, Emmerling MR (1996) J Biol Chem 271:20631–20635 Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Proc Natl Acad Sci USA 82:4245–4249 This geometry does not induce strain in the peptide backbone, making it the most likely representation of that portion of the Cu 2+–Aβ complex monomer in aqueous solution. In solution at pH=7, Cu 2+ promotes the deprotonation and involvement in the binding of the backbone amide nitrogen in a β-sheet like structure. These structures are fairly rigid and the implications for conformational changes to the Aβ backbone are discussed. Calculations show that when Cu(H 2O) 2+ 4 combines with the model compound 1 (3-(1 H-imidazol-5-yl)- N- propanamide) in the aqueous phase, the most stable binding site involves the Nπ atoms of His13 and His14 as well as the carbonyl of the intervening backbone amide group. The enthalpies were calculated with the 6–311+G(2df,2p) basis set. The effects of solvation were accommodated using the CPCM method. Quantum chemical calculations using the unrestricted B3LYP hybrid density functional method with the 6–31G(d) basis set were performed for geometries, zero point energies and thermochemistry. Experimental results indicate that Aβ1–42 in particular has a very high affinity for Cu 2+, and that His13 and His14 are the two most firmly established ligands in the coordination sphere of the copper ion. The Cu 2+ concentrations in cores of senile plaques are significantly elevated in AD patients. Note that because of processes such as the post-translational modifications to proteins we still need protein sequencing and I believe that we currently rely too heavily on DNA sequencing.Two of the defining hallmarks of Alzheimer’s disease (AD) are deposits of the β-amyloid peptide, Aβ, and the generation of reactive oxygen species, both of which may be due to the Aβ peptide coordinating metal ions. This is because it is now much easier to sequence DNA. Instead, since it has been worked out (mostly) how DNA codes for protein, we usually infer the protein sequence from the DNA sequence. However, it is now relatively rare to directly determine protein sequence! The very first protein sequence (bovine insulin) was determined by Fredrick Sanger in 1951-2 (note that this was more than a decade before the first nucleotide sequence). There are many different techniques for directly determining protein sequences - this wikipedia article is a decent introduction: ![]() There are also methods that have been developed to remove amino acids one at a time.īy combining theses techniques it is possible to directly determine protein sequences. This is a great question, but actually quite complicated so I'm not going to try to give a complete answer - I have given some useful links below if you wish to learn more.Įach amino acid has unique chemical properties that can be used to tell them apart.
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