RESUMO
The self-assembly of a peptide based on a sequence from the amyloid beta peptide but incorporating the non-natural amino acid beta-2-thienylalanine (2-Thi) has been investigated in aqueous and methanol solutions. The peptide AAKLVFF was used as a design motif, replacing the phenylalanine residues (F) with 2-Thi units to yield (2-Thi)(2-Thi)VLKAA. The 2-Thi residues are expected to confer interesting electronic properties due to charge delocalization and pi-stacking. The peptide is shown to form beta-sheet-rich amyloid fibrils with a twisted morphology, in both water and methanol solutions at sufficiently high concentration. The formation of a self-assembling hydrogel is observed at high concentration. Detailed molecular modeling using molecular dynamics methods was performed using NOE constraints provided by 2D-NMR experiments. The conformational and charge properties of 2-Thi were modeled using quantum mechanical methods, and found to be similar to those previously reported for the beta-3-thienylalanine analogue. The molecular dynamics simulations reveal well-defined folded structures (turn-like) in dilute aqueous solution, driven by self-assembly of the hydrophobic aromatic units, with charged lysine groups exposed to water.
Assuntos
Alanina/análogos & derivados , Peptídeos beta-Amiloides/química , Peptídeos/química , Estrutura Secundária de Proteína , Alanina/química , Sequência de Aminoácidos , Peptídeos beta-Amiloides/genética , Dicroísmo Circular , Microscopia Crioeletrônica , Hidrogéis/química , Microscopia de Força Atômica , Modelos Moleculares , Simulação de Dinâmica Molecular , Estrutura Molecular , Peptídeos/genética , Espalhamento a Baixo Ângulo , Espectrometria de Fluorescência , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios XRESUMO
A series of molecular dynamics simulations in aqueous solution have been carried out in order to investigate the effects of the length of the peptide chain and the temperature on the helical conformation of un-ionized poly(gamma-D-glutamic acid). The results reveal that the helix is not stable for a small number of residues independent of the temperature. On the other hand, the temperature induces a conformational transition from the helical state to the random coil. Analysis of the energy of the whole system indicates that the helix is more stable than the random coil state by about 5 kcal/mol, even although the solvation potential energy is lower in the latter than in the former.
Assuntos
Ácido Poliglutâmico/química , Biopolímeros/química , Modelos Moleculares , Conformação Proteica , Estrutura Secundária de Proteína , Soluções , Termodinâmica , ÁguaRESUMO
The conformational preferences of the naturally occurring poly(gamma-D-glutamic acid) in the un-ionized state were investigated using a combination of molecular dynamics and quantum mechanical calculations. Results indicated that a left-handed helix with 19-membered ring hydrogen bonds set between the CO of the amide group i and the NH of amide group i + 3 is the most stable conformation for this poly(gamma-amino acid). Weak intramolecular interactions between the oxygens of the carboxyl side groups and the NH of the backbone amide groups were detected. They are assumed to be responsible for the unexpected handedness exhibited by the helix with regards to the stereochemistry of the compound.