The polyphenols curcumin (CU) and ferulic acid (FA) are able to inhibit the aggregation of amyloid-ß (Aß) peptide with different strengths. CU is a strong inhibitor while FA is a weaker one. In the present study, we examine the effects of CU and FA on the folding process of an Aß monomer by 1 µs molecular dynamics (MD) simulations. We found that both inhibitors increase the helical propensity and decrease the non-helical propensity of Aß peptide. They prevent the formation of a dense bulk core and shorten the average lifetime of intramolecular hydrogen bonds in Aß. CU makes more and longer-lived hydrogen bonds, hydrophobic, π-π, and cation-π interactions with Aß peptide than FA does, which is in a good agreement with the observed stronger inhibitory activity of CU on Aß aggregation.
Amyloid beta-Peptides/chemistry , Coumaric Acids/pharmacology , Curcumin/pharmacology , Protein Folding , Coumaric Acids/chemistry , Curcumin/chemistry , Hydrogen Bonding , Ligands , Models, Molecular , Protein Folding/drug effects , Protein Stability/drug effects , Protein Structure, Secondary , Solvents , Static Electricity
The amyloid plaques are a key hallmark of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Amyloidogenesis is a complex long-lasting multiphase process starting with the formation of nuclei of amyloid peptides: a process assigned as a primary nucleation. Curcumin (CU) is a well-known inhibitor of the aggregation of amyloid-beta (Aß) peptides. Even more, CU is able to disintegrate preformed Aß firbils and amyloid plaques. Here, we simulate by molecular dynamics the primary nucleation process of 12 Aß peptides and investigate the effects of CU on the process. We found that CU molecules intercalate among the Aß chains and bind tightly to them by hydrogen bonds, hydrophobic, π-π, and cation-π interactions. In the presence of CU, the Aß peptides form a primary nucleus of a bigger size. The peptide chains in the nucleus become less flexible and more disordered, and the number of non-native contacts and hydrogen bonds between them decreases. For comparison, the effects of the weaker Aß inhibitor ferulic acid (FA) on the primary nucleation are also examined. Our study is in good agreement with the observation that taken regularly, CU is able to prevent or at least delay the onset of neurodegenerative disorders.
Amyloid beta-Peptides/chemistry , Curcumin/pharmacology , Neuroprotective Agents/pharmacology , Protein Aggregates/drug effects , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/prevention & control , Amyloid/antagonists & inhibitors , Amyloid/chemistry , Amyloid/metabolism , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Binding Sites , Coumaric Acids/chemistry , Coumaric Acids/pharmacology , Curcumin/chemistry , Humans , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Neuroprotective Agents/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs
BACKGROUND: Adaptive mutations that alter protein functionality are enriched within intrinsically disordered protein regions (IDRs), thus conformational flexibility correlates with evolvability. Pre-structured motifs (PreSMos) with transient propensity for secondary structure conformation are believed to be important for IDR function. The glucocorticoid receptor tau1core transcriptional activation domain (GR tau1core) domain contains three α-helical PreSMos in physiological buffer conditions. METHODS: Sixty change-of-function mutants affecting the intrinsically disordered 58-residue GR tau1core were studied using disorder prediction and molecular dynamics simulations. RESULTS: Change-of-function mutations were partitioned into seven clusters based on their effect on IDR predictions and gene activation activity. Some mutations selected from clusters characterized by mutations altering the IDR prediction score, altered the apparent stability of the α-helical form of one of the PreSMos in molecular dynamics simulations, suggesting PreSMo stabilization or destabilization as strategies for functional adaptation. Indeed all tested gain-of-function mutations affecting this PreSMo were associated with increased stability of the α-helical PreSMo conformation, suggesting that PreSMo stabilization may be the main mechanism by which adaptive mutations can increase the activity of this IDR type. Some mutations did not appear to affect PreSMo stability. CONCLUSIONS: Changes in PreSMo stability account for the effects of a subset of change-of-function mutants affecting the GR tau1core IDR. GENERAL SIGNIFICANCE: Long IDRs occur in about 50% of human proteins. They are poorly characterized despite much recent attention. Our results suggest the importance of a subtle balance between PreSMo stability and IDR activity, which may provide a novel target for future pharmaceutical intervention.
Intrinsically Disordered Proteins/chemistry , Molecular Dynamics Simulation , Mutation , Protein Conformation, alpha-Helical , Receptors, Glucocorticoid/chemistry , Humans , Intrinsically Disordered Proteins/genetics , Receptors, Glucocorticoid/genetics , Transcriptional Activation
Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aß) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Aß aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω-loop of Aß binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Galantamine/chemistry , Galantamine/pharmacology , Acetylcholinesterase/chemistry , Animals , Blood-Brain Barrier/metabolism , Camphanes/chemistry , Camphanes/pharmacokinetics , Camphanes/pharmacology , Cell Line , Cholinesterase Inhibitors/pharmacokinetics , Electrophorus , Galantamine/pharmacokinetics , Humans , Mice , Molecular Docking Simulation
The preference of ß-fluoroimines to adopt a gauche conformation has been studied by single-crystal X-ray diffraction analysis and DFT methods. Empirical and theoretical evidence for a preferential gauche arrangement around the NCCF torsion angle (φ) is presented ((E)-2-fluoro-N-(4-nitrobenzylidene)ethanamine: φ(NCCF) =70.0°). In the context of this study, the analysis of a pyridoxal-derived ß-fluoroaldimine was performed, a species that is implicated in the inhibition of pyridoxal phosphate (PLP)-dependent enzymes by ß-fluoroamine derivatives. The gauche preference of the internal aldimine (=NCH(2)CH(2)F) that can be rationalized by stereoelectronic arguments does not hold for the corresponding external system (N=CHCH(2)F) (E(min) when φ(NCCF) =120°). Moreover, the C-F bond is lengthened by more than 0.02 Å at φ(NCCF) =±90°, when it is exactly antiperiplanar to the conjugated imine. This activation of the C-F σ bond by an adjacent π system constitutes an addendum to Dunathan's stereoelectronic hypothesis.
Fluorine/chemistry , Hydrocarbons, Fluorinated/chemistry , Models, Chemical , Crystallography, X-Ray/methods , Imines/chemistry , Molecular Conformation , Stereoisomerism
