title: A molecular dynamics study of the interaction of D-peptide amyloid inhibitors with their target sequence reveals a potential inhibitory pharmacophore conformation.
abstract: The self-assembly of soluble proteins and peptides into beta-sheet-rich oligomeric structures and insoluble fibrils is a hallmark of a large number of human diseases known as amyloid diseases. Drugs that are able to interfere with these processes may be able to prevent and/or cure these diseases. Experimental difficulties in the characterization of the intermediates involved in the amyloid formation process have seriously hampered the application of rational drug design approaches to the inhibition of amyloid formation and growth. Recently, short model peptide systems have proved useful in understanding the relationship between amino acid sequence and amyloid formation using both experimental and theoretical approaches. Moreover, short D-peptide sequences have been shown to specifically interfere with those short amyloid stretches in proteins, blocking oligomer formation or disassembling mature fibrils. With the aim of rationalizing which interactions drive the binding of inhibitors to nascent beta-sheet oligomers, in this study, we have carried out extensive molecular dynamics simulations of the interaction of selected d-peptide sequences with oligomers of the target model sequence STVIIE. Structural analysis of the simulations helped to identify the molecular determinants of an inhibitory core whose conformational and physicochemical properties are actually shared by nonpeptidic small-molecule inhibitors of amyloidogenesis. Selection of one of these small molecules and experimental validation against our model system proved that it was indeed an effective inhibitor of fibril formation by the STVIIE sequence, supporting theoretical predictions. We propose that the inhibitory determinants derived from this work be used as structural templates in the development of pharmacophore models for the identification of novel nonpeptidic inhibitors of aggregation.
authors.affiliation: Computational and Structural Biology Unit, European Molecular Biology Laboratory, Heidelberg, Baden-Württemberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Esteras-Chopo
authors.forename: Giulia
authors.initials: G
authors.lastname: Morra
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Moroni
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.forename: Manuela
authors.initials: M
authors.lastname: Lopez de la Paz
authors.forename: Giorgio
authors.initials: G
authors.lastname: Colombo
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000187:drug effects*; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D000682:Amyloid; D009842:Oligopeptides