Oligomers of A␤ peptides are suspected as the underlying cause of Alzheimer disease. Knowledge of their structural properties could therefore lead to a deeper understanding of the mechanism behind the outbreak of this disease. As a step in this direction we have studied A␤ dimers by all-atom molecular dynamics simulations. Equilibrated structures at 300 K were clustered into different families with similar structural features. The dominant cluster has parallel N-terminals and a well defined segment Leu17-Ala21 that are stabilized by salt bridges between Lys28 of one chain and either Glu22 or Asp23 of the other chain. The formation of these salt bridges may be the limiting step in oligomerization and fibrillogenesis.

Results from replica-exchange and regular room temperature molecular dynamics simulations of the Alzheimer's ␤ amyloid ͑A␤ 1-39 ͒ monomer in an implicit solvent are reported. Our data indicate that at room temperature, the monomer assumes random-coil and soluble conformations. No beta content is observed which therefore seems to be a product of oligomerization and aggregation of monomers.

Conformational studies of the peptides constructed from achiral amino acid residues Aib and Delta(Z)Phe (I) Ac-Aib-Delta(Z)Phe-NHMe (II), and Ac-(Aib-Delta(Z)Phe)(3)-NHMe; peptides III-VI having L-Leu or D-Leu at either the N- or the C-terminal position and of peptides VII-X having Leu residues in different enantiomeric combinations at both the N- and the C-terminal positions in peptide II have been studied to design the peptide with the required helical sense. Peptide II, as expected, adopts degenerate left- and right-handed helical structures. It has been shown that the peptides IV and VI having D-Leu at either the N or the C terminus can be realized in the right-handed helical structure with the phi,psi values of -20 degrees and -60 degrees for the Aib/Delta(Z)Phe residues. L-Leu and D- Leu at both the terminals in peptides VII and VIII, respectively, have hardly any effect as both the left- and the right-handed structures are found to be degenerate. Peptides III and IX can be realized in right- and left-handed helical structures, respectively, in solvents of low polarity whereas peptides V and X are predicted to be in the right-handed helical structures stabilized by carbonyl-carbonyl interactions without the formation of hydrogen bonds. The conformational states with the phi,psi values of 0 degrees and -85 degrees in peptide V are characterized by rise per residue of 2.03 A, rotation per residue of 117.5 degrees , and 3.06 residues per turn. In all peptides having Leu residue at the N terminus, the methyl moiety of the acetyl group is involved in the CH/pi interactions with the Cepsilon--Cdelta edge of the aromatic ring of Delta(Z)Phe (3) and the amino group NH of Delta(Z)Phe is involved in the NH/pi interactions with its own aromatic ring. The CH(3) groups of the Aib residues are also involved in CH/pi interactions with the i + 1th and i + 3th Delta(Z)Phe's aromatic side chains.

: The hydration of urea and guanidium ion have been studied by quantum chemical and molecular mechanics methods. The hydration of urea takes place only through the amino groups and not through the carbonyl group. One mole of urea decreases the free concentration of water by seven moles and one mole of guanidium ion by twelve moles. The interaction energies (AE's) for the hydration of urea and guanidium ion in both the primary and secondary spheres are more than that of waterwater interactions. Also, the interaction energy of urea and guanidium ion with water is more than the interaction energy of urea and guanidium ion with the potential hydrogen bonding sites in the peptide groups of the model pentapeptides. The "collagen type structure" (with &=-300, ~i=1200) has been taken as model for hnctional domain which is stabilized by interaction with water through free potential hydrogen bonding sites. It is shown that these denaturants, reduce the free concentratiodactivity of water effectively and remove the water molecules from the protein surface. The computational results also demonstrate why lower concentrations of guanidium ion is sufficient to bring about the denaturation in comparison to urea. The interaction studies also reveal that there is no complex formation between the peptides groups and denaturant molecules. The cause of protein aggregation in the presence of denaturants and hence, the loss of biological activity is also discussed.

␣,␤-Unsaturated amino acids dehydroamino acids have been found in naturally occurring antibiotics of microbial origin and in some proteins. Due to the presence of the C C double bond, the dehydroamino acids influence the main-chain between C O of the acetyl group and the NH of the amide group, resulting in the formation of a 10-membered ring. In the model heptapeptide containing ⌬ Ala at alternate position with Ala, Abu, and Leu, the lowest-energy conformation corresponds to s y30Њ and s 120Њ for all the Ala, Abu, and Leu residues and s s 30Њ for all ⌬ Ala residues. A graphical view of the molecule in this conformation reveals the formation of three hydrogen bonds involving the C O moiety of the ith residue and the NH moiety of the i q 3th residue, resulting in a 10-membered ring formation. In this structure, only alternate peptide bonds are involved in the intramolecular hydrogen-bond formation unlike the helices and it has been named the ␤-bend ribbon structure. The helical structures were predicted to be the most stable structures in the heptapeptide Ž . Ac᎐ Aib᎐⌬Ala ᎐NHMe with s "30Њ, s "60Њ for Aib residues and s s "30Њ 3 for ⌬ Ala residues. The computational results reveal that the ⌬ Ala residue does not induce an inverse ␥-turn in the preceding residue. It is the competitive interaction of small solvent molecules with the hydrogen-bonding sites of the peptide which gives rise Ž . to the formation of an inverse ␥-turn s y54Њ, s 82Њ; s 44Њ, s 3Њ in the 1 1 2 2 preceding residue to ⌬ Ala. The computational studies for the positional preference of ⌬ Ala in the peptide containing one ⌬ Ala and nine Ala residues reveals the formation of

alpha,beta-Dehydroamino acid residues due to the presence of Calpha = Cbeta double bond influences the main chain and the side chain conformations. These residues have interesting chemical features including the increased resistance to enzymatic degradation. The chain length dependent conformational behavior of poly alpha,beta-dehydroleucine (DeltaLeu) peptides in both the pure forms Z and E and their various combinations like alternate ZE/EZ etc. have been investigated by using quantum mechanical method PCILO (perturbative configuration interaction of localized orbitals). The conformational states in alternate Z and E forms, with Phi, Psi values of -10 degrees , 105 degrees /1 degrees , -88 degrees for Z form and 35 degrees , 22 degrees /-34 degrees , -27 degrees for the E form are found to be the most stable and degenerate than the states in pure Z and E forms and the EZ form etc. The repeated Phi, Psi values give rise to altogether new types of left and right handed helices, and their stability increases with increasing chain length. These structures are stabilized by intramolecular hydrogen bonding, carbonyl-carbonyl interactions and hydrophobic interactions between the side chains of DeltaZLeu and DeltaELeu residues. The 2(7) ribbon structure (seven-membered hydrogen-bonded ring involving two consecutive amino acid residues) is found to be most stable and degenerate in the pentapeptide Ac-DeltaELeu5-NHMe, due to the formation of maximum hydrogen bonds. A right-handed template from achiral DeltaLeu peptides has been achieved by incorporating L-Leu at the C-terminal or D-Leu at the N-terminal.

Aliphatic homo-polypeptoids of NAla, NVal, NIle and NLeu both in the presence and absence of protecting groups adopt helical structures without hydrogen bonds with Φ, Ψ values of ~ 0, ± 90° with trans amide bonds. These structures are stabilized by carbonyl-carbonyl interactions and characterized by ~ 3.16 residues per turn with a pitch of ~ 6.13 Å. It has been shown that like polyvaline and polyleucine peptides, poly-peptoids can also be exploited for the construction of potential surfactant like molecules by incorporating charged amino acid residues at the N terminal. A single-handed template with Φ, Ψ values of ~ 0, 90° can be attained by incorporating L-leu or L-val at the C-terminal of poly-NIle. Analysis of the simulation results in water as a function of time reveals that the opening of helical structures without hydrogen bonds takes place at sub-picosecond time scale starting from the N-terminal. This leads to the formation of collagen or inverse-collagen type structures (Φ, Ψ ~ -60, 145° and 60, -145° respectively) stabilized by interactions of water molecules with the backbone carbonyl groups

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