Amyloid structure

2014 ◽  
Vol 56 ◽  
pp. 1-10 ◽  
Author(s):  
Louise Serpell
Keyword(s):  
Hydrogen Bonding ◽  
Sequence Homology ◽  
Amyloid Fibrils ◽  
Side Chains ◽  
Primary Sequence ◽  
Sheet Structure ◽  
Β Sheets ◽  
The Stability ◽  
Β Sheet ◽  
Proteins And Peptides

Amyloid fibrils are formed by numerous proteins and peptides that share little sequence homology. The structures formed are highly ordered and extremely stable, being composed of β-sheet structure and stabilized along their length by hydrogen bonding. The fibrils are formed by several protofilaments that wind around one another in rope-like structures, lending further strength and stability to the resulting fibres. The fact that so many proteins and peptides form amyloid structures under suitable conditions, seems to suggest that the sequence of the precursor is unimportant. However, it is now clear that side chains play a central role in forming interactions between several β-sheets to further stabilize and regulate the structures. The primary sequence plays a central role in determining the rate of fibril formation, the stability of the resulting structure to degradation and the final morphology of the fibrils. The side chains regulate the elongation and growth, and also the lateral association of the protofilament and fibrils, having a significant impact on the final architecture.

STRUCTURAL INSIGHT INTO THE POLYMORPHISM OF NNQNTF PROTOFIBRIL: IMPORTANCE OF INTERFACIAL WATER, POLAR AND AROMATIC RESIDUES

2013 ◽  
Vol 12 (08) ◽  
pp. 1341012
Author(s):  
YAN LU ◽  
WENHUI XI ◽  
GUANGHONG WEI
Keyword(s):  
Hydrogen Bonding ◽  
Amyloid Fibrils ◽  
Md Simulations ◽  
Side Chains ◽  
Face To Face ◽  
Recent Experimental Study ◽  
Aromatic Stacking ◽  
Detailed Structural Analysis ◽  
Physical Interactions ◽  
Β Sheets

Polymorphism is widely observed in amyloid fibrils associated with many neurodegenerative diseases. Recent experimental study reported that fibrils formed by the segment NNQNTF of elk prion protein exhibited facial polymorphism with the two β-sheets either in back-to-back (BB) or in face-to-face (FF) packing arrangement. In the BB packing, the side chains of N2, N4 and F6 are interdigitated to form steric zipper, while in the FF packing, the side chains of N1, Q3 and T5 form the interdigitated interface. In this study, we investigate the water-mediated assembly of two preformed β-sheets and the physical interactions that stabilize the two different fibrils using all-atom molecular dynamics (MD) simulations. Multiple MD simulations have been carried out by starting from FF or BB packing of two β-sheets according to the facial polymorphism revealed by X-ray microcrystallography. For both packing patterns, we observe that the assembly of β-sheets is mediated by water molecules in the interface between β-sheets, leading to a long-lived protofibrils with wet interface prior to the formation of dry amyloid fibrils. Detailed structural analysis shows that besides the side chain steric zipper interactions, intra-sheet hydrogen bonding and aromatic stacking interactions play an important role on the stabilization of the protofibril with BB packing, while the intra-sheet and inter-sheet hydrogen bonding interactions are crucial for the formation of BB protofibril. These findings provide insights into the mechanism that lead to the facial polymorphism of NNQNTF fibrils.

scholarly journals Factors involved in the stability of isolated β-sheets: Turn sequence, β-sheet twisting, and hydrophobic surface burial

2004 ◽  
Vol 13 (4) ◽  
pp. 1134-1147 ◽  
Author(s):  
Clara M. Santiveri ◽  
Jorge Santoro ◽  
Manuel Rico ◽  
M. Angeles Jiménez
Keyword(s):  
Hydrophobic Surface ◽  
Β Sheets ◽  
The Stability ◽  
Β Sheet

NMR structure of bucandin, a neurotoxin from the venom of the Malayan krait (Bungarus candidus)

2001 ◽  
Vol 360 (3) ◽  
pp. 539-548 ◽  
Author(s):  
Allan M. TORRES ◽  
R. Manjunatha KINI ◽  
Nirthanan SELVANAYAGAM ◽  
Philip W. KUCHEL
Keyword(s):  
Solution Structure ◽  
Pharmacological Action ◽  
Nmr Structure ◽  
Side Chains ◽  
X Ray ◽  
Nmr Study ◽  
C Terminus ◽  
Mean Structure ◽  
Β Sheets ◽  
Β Sheet

A high-resolution solution structure of bucandin, a neurotoxin from Malayan krait (Bungarus candidus), was determined by 1H-NMR spectroscopy and molecular dynamics. The average backbone root-mean-square deviation for the 20 calculated structures and the mean structure is 0.47 Å (1 Å = 0.1nm) for all residues and 0.24 Å for the well-defined region that spans residues 23–58. Secondary-structural elements include two antiparallel β-sheets characterized by two and four strands. According to recent X-ray analysis, bucandin adopts a typical three-finger loop motif and yet it has some peculiar characteristics that set it apart from other common α-neurotoxins. The presence of a fourth strand in the second antiparallel β-sheet had not been observed before in three-finger toxins, and this feature was well represented in the NMR structure. Although the overall fold of the NMR structure is similar to that of the X-ray crystal structure, there are significant differences between the two structures that have implications for the pharmacological action of the toxin. These include the extent of the β-sheets, the conformation of the region spanning residues 42–49 and the orientation of some side chains. In comparison with the X-ray structure, the NMR structure shows that the hydrophobic side chains of Trp27 and Trp36 are stacked together and are orientated towards the tip of the middle loop. The NMR study also showed that the two-stranded β-sheet incorporated in the first loop, as defined by residues 1–22, and the C-terminus from Asn59, is probably flexible relative to the rest of the molecule. On the basis of the dispositions of the hydrophobic and hydrophilic side chains, the structure of bucandin is clearly different from those of cytotoxins.

scholarly journals Synthesis and binding studies of two new macrocyclic receptors for the stereoselective recognition of dipeptides

2010 ◽  
Vol 6 ◽  
Author(s):  
Ana Maria Castilla ◽  
M Morgan Conn ◽  
Pablo Ballester
Keyword(s):  
Hydrogen Bonding ◽  
Peptide Ligands ◽  
Binding Studies ◽  
Design Synthesis ◽  
Macrocyclic Receptors ◽  
H Nmr ◽  
Hydrogen Bonding Pattern ◽  
Conformational Equilibria ◽  
Β Sheets ◽  
Β Sheet

We present here the design, synthesis, and analysis of a series of receptors for peptide ligands inspired by the hydrogen-bonding pattern of protein β-sheets. The receptors themselves can be regarded as strands 1 and 3 of a three-stranded β-sheet, with cross-linking between the chains through the 4-position of adjacent phenylalanine residues. We also report on the conformational equilibria of these receptors in solution as well as on their tendency to dimerize. 1H NMR titration experiments are used to quantify the dimerization constants, as well as the association constant values of the 1:1 complexes formed between the receptors and a series of diamides and dipeptides. The receptors show moderate levels of selectivity in the molecular recognition of the hydrogen-bonding pattern present in the diamide series, selecting the α-amino acid-related hydrogen-bonding functionality. Only one of the two cyclic receptors shows modest signs of enantioselectivity and moderate diastereoselectivity in the recognition of the enantiomers and diastereoisomers of the Ala-Ala dipeptide (ΔΔG 0 1 (DD-DL) = −1.08 kcal/mol and ΔΔG 0 1 (DD-LD) = −0.89 kcal/mol). Surprisingly, the linear synthetic precursors show higher levels of stereoselectivity than their cyclic counterparts.

scholarly journals Far-Off Resonance: Multiwavelength Raman Spectroscopy Probing Amide Bands of Amyloid-β-(37–42) Peptide

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3556
Author(s):  
Martynas Talaikis ◽  
Simona Strazdaitė ◽  
Mantas Žiaunys ◽  
Gediminas Niaura
Keyword(s):  
Raman Spectroscopy ◽  
Conformational Changes ◽  
Relative Intensity ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Intensity Increase ◽  
Amyloid Β Peptide ◽  
Peptide Backbone ◽  
Sheet Structure ◽  
Β Sheet

Several neurodegenerative diseases, like Alzheimer’s and Parkinson’s are linked with protein aggregation into amyloid fibrils. Conformational changes of native protein into the β-sheet structure are associated with a significant change in the vibrational spectrum. This is especially true for amide bands which are inherently sensitive to the secondary structure of a protein. Raman amide bands are greatly intensified under resonance conditions, in the UV spectral range, allowing for the selective probing of the peptide backbone. In this work, we examine parallel β-sheet forming GGVVIA, the C-terminus segment of amyloid-β peptide, using UV–Vis, FTIR, and multiwavelength Raman spectroscopy. We find that amide bands are enhanced far from the expected UV range, i.e., at 442 nm. A reasonable two-fold relative intensity increase is observed for amide II mode (normalized according to the δCH2/δCH3 vibration) while comparing 442 and 633 nm excitations; an increase in relative intensity of other amide bands was also visible. The observed relative intensification of amide II, amide S, and amide III modes in the Raman spectrum recorded at 442 nm comparing with longer wavelength (633/785/830 nm) excited spectra allows unambiguous identification of amide bands in the complex Raman spectra of peptides and proteins containing the β-sheet structure.

scholarly journals Nanostructure and stability of calcitonin amyloids

2017 ◽  
Vol 292 (18) ◽  
pp. 7348-7357 ◽  
Author(s):  
Federica Rigoldi ◽  
Pierangelo Metrangolo ◽  
Alberto Redaelli ◽  
Alfonso Gautieri
Keyword(s):  
Amyloid Fibrils ◽  
Md Simulations ◽  
Full Length ◽  
Structural Basis ◽  
Human Calcitonin ◽  
Nmr Data ◽  
Parallel Arrangement ◽  
Β Sheets ◽  
Α Helix ◽  
Β Sheet

Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp15 and Phe19 aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.

Sign in / Sign up

Export Citation Format

Share Document