β‑<i>N</i>‑Methylamino‑l‑alanine (BMAA) Not Involved in Alzheimer’s Disease

β-<i>N</i>-Methylamino-l-alanine (BMAA) is a neurotoxic agent implicated in ALS as well as Parkinson’s and Alzheimer’s diseases. It is produced by blue-green algae and could find its way via fish and seafood into the human food supply. Isolation from biological samples yields the compound in monomeric and protein-bound form. It has been suggested that the protein-bound fraction may result from genetic misincorporation into proteins in place of serine. Concomitant misfolding of the mutated proteins may be responsible for the neurological diseases. Recent reports that contradict the misincorporation theory leave unresolved the nature of the protein-bound form of BMAA. We have found from quantum mechanical calculations on model systems that it is possible to bind BMAA with high affinity in a noncovalent fashion to proteins. Because of our interest in Alzheimer’s disease, molecular dynamics simulations were applied to search for such binding between BMAA and the β-amyloid peptide and to discover whether replacement of either of its two serine residues could affect its aggregation into neurotoxic oligomers. No stable noncovalently bound complex was found, and it was concluded that incorporation of BMAA in place of serine would not alter the conformational dynamics of the β-amyloid peptide

The Binding of Fe(II)–Heme to the Amyloid Beta Peptide of Alzheimer’s Disease: QM/MM Investigations

The structures of complexes between Aβ(1–42) and ferroheme (Fe­(II)–heme) were determined by application of Amber and ONIOM­(B3LYP/6-31G­(d):Amber) methodology. Attachment at each of the three His residues was investigated. In each case, direct bonding of the iron to the His residue is augmented by the formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of Aβ (at His13, by Lys16 and the N-terminus; at His14, by both Lys16 and Lys28; at His6, by Arg5) or by H-bonding and hydrophobic interactions (at His6, by Asp7 or Phe20). The results indicate a slight preference for His13 followed by His6 and His14, with the lowest eight structures lying within 36 kJ mol^–1 of each other. The methodology is not precise enough to permit a definitive statement as to the relative stabilities, nor to the absolute binding affinities, which are predicted to be less than 70 kJ mol^–1. The results bear on the question of how heme and copper may bind simultaneously to Aβ. They confirm that the <i>reduced</i> species can bind independently, Cu⁺ at His13–His14 and Fe­(II)–heme at His6

The Structures and Stabilities of the Complexes of Biologically Available Ligands with Fe(II) Porphine: An Ab Initio Study

Fe­(II) porphine complexes were investigated at the “MP2/LB”//B3LYP/SB level of theory where SB and LB denote the small and large basis sets, 6-31+G­(d) and 6-311+G­(2df,2p), respectively. Solvation effects due to water and benzene were approximated by the IEFPCM procedure. Ligands included H₂O, Cl^–, and OH^– and Im (imidazole), CH₃NH₂, (CH₃)₂S, CH₃CO₂^–, CH₃S^–, and CH₃PhO^– as models of the side chains of His, Lys, Met, Asp/Glu, Cys, and Tyr residues, respectively. Fe­(II) porphine, <b>2</b>, and the complexes <b>2</b>(H₂O), <b>2</b>(Im), <b>2</b>(CH₃)₂S), <b>2</b>(CH₃NH₂), and <b>2</b>(H₂O)₂ have triplet ground states. All pentacoordinated complexes of <b>2</b> with negatively charged ligands have high spin quintet ground states, while all hexacoodinated complexes with at least one Im ligand have low spin singlet ground states. With the exception of <b>2</b>(Im)₂ and <b>2</b>(Im)­((CH₃)₂S), no hexacoordinated complexes are stable in water or benzene. Redox properties are sensitive to the nature of the environment and the ligand(s) attached to the iron center. With the exception of the parent system, <b>2</b>^<b>+</b>/<b>2</b>, all complexes are predicted to have a negative reduction potential relative to the standard hydrogen electrode in water. With neutral ligand(s), the reduction potential is higher in the nonpolar environment. The opposite is true with negatively charged ligands. The redox activity of cytochromes, peroxidases, and catalases is discussed in the context of the model parent systems

Fe(III)–Heme Complexes with the Amyloid Beta Peptide of Alzheimer’s Disease: QM/MM Investigations of Binding and Redox Properties of Heme Bound to the His Residues of Aβ(1–42)

Pursuant to our previous paper [<i>J. Chem. Theory Comput.</i> <b>2012</b>, <i>8</i>, 5150–5158], the structures of complexes between Aβ(1–42) and ferriheme (Fe­(III)–heme–H₂O) were determined by application of Amber and ONIOM­(B3LYP/6-31G­(d):Amber) methodology. Attachment at each of the three His residues was investigated. As well as direct bonding of the iron to the His residue, bonding is augmented by formation of secondary salt bridges between the carboxylate groups of the heme and positively charged residues of Aβ (at His13, by Lys16 and the N-terminus; at His14, by Lys16; at His6, by Arg5). The results indicate a slight preference for His13 followed by His6 and His14, with the lowest 10 structures lying within 30 kJ mol^–1 of each other. The absolute binding affinities are predicted to be approximately 30–40 kJ mol^–1. Standard reduction potentials (<i>E</i>°) are calculated for various Fe­(III)/Fe­(II) couples. Regardless of the point of attachment of the heme, <i>E</i>° values are approximately −0.6 V relative to the standard hydrogen electrode

Copper(I) Chelators for Alzheimer’s Disease

A component of the neurotoxicity of the beta amyloid peptide (Aβ) of Alzheimer’s disease is its ability to generate superoxide, hydrogen peroxide, and hydroxyl radicals by reaction of its reduced copper complex Aβ/Cu⁺ with molecular oxygen. The objective of the present work was to devise compounds, L, that could remove Cu⁺ from Aβ/Cu⁺, with the property that L/Cu⁺ itself would not be capable of reducing O₂ or hydrogen peroxide. We show by density functional calculations that several pincer-type compounds with two imidazole rings and a sulfur or nitrogen have the desired combination of Cu⁺ binding affinity and Cu²⁺ reduction potential

NMR and Computational Studies of the Configurational Properties of Spirodioxyselenuranes. Are Dynamic Exchange Processes or Temperature-Dependent Chemical Shifts Involved?

Spirodioxyselenurane <b>4a</b> and several substituted analogs revealed unexpected ¹H NMR behavior. The diastereotopic methylene hydrogens of <b>4a</b> appeared as an AB quartet at low temperature that coalesced to a singlet upon warming to 267 K, suggesting a dynamic exchange process with a relatively low activation energy. However, DFT computational investigations indicated high activation energies for exchange via inversion through the selenium center and for various pseudorotation processes. Moreover, the NMR behavior was unaffected by the presence of water or acid catalysts, thereby ruling out reversible Se–O or benzylic C–O cleavage as possible stereomutation pathways. Remarkably, when <b>4a</b> was heated beyond 342 K, the singlet was transformed into a new AB quartet. Further computations indicated that a temperature dependence of the chemical shifts of the diastereotopic protons results in convergence upon heating, followed by crossover and divergence at still higher temperatures. The NMR behavior is therefore not due to dynamic exchange processes, but rather to temperature dependence of the chemical shifts of the diastereotopic hydrogens, which are coincidentally equivalent at intermediate temperatures. These results suggest the general need for caution in ascribing the coalescence of variable-temperature NMR signals of diastereotopic protons to dynamic exchange processes that could instead be due to temperature-dependent chemical shifts and highlight the importance of corroborating postulated exchange processes through additional computations or experiments wherever possible