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\begin{document}

\title{Metastable Alpha-rich and Beta-rich Conformations of Small A\selectlanguage{greek}β\selectlanguage{english}42 Peptide
Oligomers\selectlanguage{english}}



\author[1]{Philippe Derreumaux}%
\author[1]{Phuong Nguyen}%
\author[1]{Fabio Sterpone}%
\affil[1]{Institut de Biologie Physico-Chimique}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Probing the structures of amyloid-beta (A\selectlanguage{greek}β\selectlanguage{english}) peptides in the early steps
of aggregation is extremely difficult experimentally and
computationally. Yet, this knowledge is extremely important as small
oligomers are the most toxic species. Experiments and simulations on
A\selectlanguage{greek}β\selectlanguage{english}42 monomer point to random coil conformations with either transient
helical or \selectlanguage{greek}β-\selectlanguage{english}strand content. Our current conformational description of
small A\selectlanguage{greek}β\selectlanguage{english}42 oligomers is funneled toward amorphous aggregates with some
\selectlanguage{greek}β-\selectlanguage{english}sheet content and rare excited states with well-ordered assemblies of
\selectlanguage{greek}β-\selectlanguage{english}sheets. In this study, we emphasize another view based on metastable
\selectlanguage{greek}α-\selectlanguage{english}helix bundle oligomers spanning the C-terminus residues which are
predicted by the machine-learning AlphaFold2 method and supported
indirectly by low-resolution experimental data on many amyloid
polypeptides. This finding has consequences in designing drugs to reduce
aggregation and toxicity.%
\end{abstract}%



\sloppy


\selectlanguage{greek}\textbf{Metastable Alpha-rich and Beta-rich Conformations of Small Aβ42
Peptide Oligomers}\selectlanguage{english}

Phuong H. Nguyen,\textsuperscript{1} Fabio
Sterpone,\textsuperscript{1}Philippe Derreumaux \textsuperscript{1,2*}

1 CNRS, Universit\selectlanguage{ngerman}é Paris Cité, UPR 9080, Laboratoire de Biochimie
Théorique, Institut de Biologie Physico-Chimique, Fondation Edmond de
Rothschild, 13 rue Pierre et Marie Curie, 75005 Paris, France.

2 Institut Universitaire de France (IUF), 75005, Paris, France.

\textbf{Abstract:} Probing the structures of amyloid-beta (A\selectlanguage{greek}β\selectlanguage{english}) peptides
in the early steps of aggregation is extremely difficult experimentally
and computationally. Yet, this knowledge is extremely important as small
oligomers are the most toxic species. Experiments and simulations on
A\selectlanguage{greek}β\selectlanguage{english}42 monomer point to random coil conformations with either transient
helical or \selectlanguage{greek}β-\selectlanguage{english}strand content. Our current conformational description of
small A\selectlanguage{greek}β\selectlanguage{english}42 oligomers is funneled toward amorphous aggregates with some
\selectlanguage{greek}β-\selectlanguage{english}sheet content and rare excited states with well-ordered assemblies of
\selectlanguage{greek}β-\selectlanguage{english}sheets. In this study, we emphasize another view based on metastable
\selectlanguage{greek}α-\selectlanguage{english}helix bundle oligomers spanning the C-terminus residues which are
predicted by the machine-learning AlphaFold2 method and supported
indirectly by low-resolution experimental data on many amyloid
polypeptides. This finding has consequences in designing drugs to reduce
aggregation and toxicity.

\textbf{Keywords:} amyloid-beta, aggregation, simulations, atomistic,
coarse-grained, small oligomers

\textbf{1.Introduction}

Amyloid-beta (A\selectlanguage{greek}β\selectlanguage{english}) peptides of 40 and 42 amino acids are proteolytically
cleaved form amyloid precursor protein by \selectlanguage{greek}β- \selectlanguage{english}and \selectlanguage{greek}γ-\selectlanguage{english}secretases. Soluble
A\selectlanguage{greek}β \selectlanguage{english}dimers isolated from Alzheimer's cortex directly induce tau
hyperphosphorylation and neuritic degeneration, and small A\selectlanguage{greek}β \selectlanguage{english}oligomers
are believed to the most toxic species.\textsuperscript{1,2} The
aggregation kinetics of A\selectlanguage{greek}β \selectlanguage{english}follows a sigmoidal curve with three phases:
a lag phase free of any Thioflavin T fluorescence signal, a growth phase
or fibril elongation followed by a saturation
phase.\textsuperscript{3,4} A\selectlanguage{greek}β\selectlanguage{english}42, less abundant but more toxic than in
its A\selectlanguage{greek}β\selectlanguage{english}40 counterpart, is very sensitive to protein concentration upon
aggregation in the bulk solution, and also pH, temperature, the presence
of membrane and the addition of seeds. Characterizing the early A\selectlanguage{greek}β
\selectlanguage{english}oligomers is challenging experimentally and
computationally.\textsuperscript{5-7}

This is an experimental challenge due to the transient and heterogeneous
ensemble of oligomer structures, the fact that most experimental
observables provide time- and space-averaged
properties,\textsuperscript{6} and the \selectlanguage{greek}µ\selectlanguage{english}s time resolution cannot be
achieved yet.\textsuperscript{8} This is a challenge for computer
simulations due to the accuracy of the protein and water force
fields,\textsuperscript{9,10} and the time scale of primary nucleation
in pure buffer which is on the order of several hours for A\selectlanguage{greek}β\selectlanguage{english}42 at \selectlanguage{greek}µ\selectlanguage{english}M
concentrations.\textsuperscript{4} By using atomistic molecular dynamics
(MD) simulations, the current time lengths vary from 2.5 to 30 \selectlanguage{greek}µ\selectlanguage{english}s for 20
A\selectlanguage{greek}β\selectlanguage{english}42 peptides with an implicit solvent model,\textsuperscript{11} and
A\selectlanguage{greek}β\selectlanguage{english}40 monomer in explicit water,\textsuperscript{12} respectively.
Simulations of A\selectlanguage{greek}β\selectlanguage{english}40/42 species with free lipids and calcium ions in
aqueous solution are also currently limited to the \selectlanguage{greek}µ\selectlanguage{english}s time
scale.\textsuperscript{13-15} Going beyond this time scale or sampling
rare events has been made possible by the use of coarse-grained or
mesoscopic models and enhanced sampling techniques such as path or
umbrella sampling and metadynamics, among others. Our current structural
view of A\selectlanguage{greek}β\selectlanguage{english}40/42 monomers and small oligomers is random coil, with
increasing \selectlanguage{greek}β-\selectlanguage{english}sheet content as the oligomer size
increases.\textsuperscript{16} In this study, we emphasize other
metastable oligomers based on \selectlanguage{greek}α-\selectlanguage{english}helix bundles that are predicted by the
AlphaFold2 machine learning and are indirectly supported by
low-resolution experimental data on many amyloid polypeptides.

\textbf{2. Results and discussion}

\textbf{2.1 Monomer}

The current experimental view we have for A\selectlanguage{greek}β\selectlanguage{english}40 and A\selectlanguage{greek}β\selectlanguage{english}42 monomers is that
they lack stable secondary and tertiary structures and have flat free
energy surfaces.\textsuperscript{17} The monomers consist of a
heterogeneous ensemble of random coil states with little \selectlanguage{greek}α-\selectlanguage{english}helix and
\selectlanguage{greek}β-\selectlanguage{english}strand character. Both extended and compact conformations were
obtained by SOP-IDP coarse-grained Langevin dynamics simulations at 300
K,\textsuperscript{18} all-atom metadynamics simulations at 350 K using
CHARMM22-TIP3P force field,\textsuperscript{19} and atomistic MD
simulations at 300 K using the AMBER99SB-disp\textsuperscript{12} and
CHARMM36m-TIP3P modified\textsuperscript{20} force fields.

Small helical contents in monomer were evidenced by many theoretical
studies. Metadynamics at 350 K applied to A\selectlanguage{greek}β\selectlanguage{english}40 monomer predicted high
energy states with \selectlanguage{greek}α-\selectlanguage{english}helix at residues 21-26 and
30-37.\textsuperscript{19} A\selectlanguage{greek}β\selectlanguage{english}42 conformations with \selectlanguage{greek}α-\selectlanguage{english}helix content
spanning residues 10-20 were predicted by the Folding@home approach
using thousands of MD simulations with the AMBER99sb-TIP3P force
field,\textsuperscript{21} and by multiple-reservoir replica exchange
simulations with the AMBER99sb/TIP4P-Ew force
field.\textsuperscript{22}Partially folded \selectlanguage{greek}α-\selectlanguage{english}helical structures spanning
the CHC (central hydrophobic core, residues 17-21) and residues 30-38 of
A\selectlanguage{greek}β\selectlanguage{english}42 were reported by MD simulations and Hamiltonian replica exchange
with solute scaling.\textsuperscript{23} A short helix covering residues
17-23 was also reported for A\selectlanguage{greek}β\selectlanguage{english}40 monomer using a predictive
coarse-grained force field.\textsuperscript{24}

Transient helical conformations were also evidenced experimentally. They
were reported by a SERS (surface enhanced Raman spectroscopy) study on
A\selectlanguage{greek}β\selectlanguage{english}40 monomer between pH 5.5 and 10.5.\textsuperscript{25} A nuclear
magnetic resonance (NMR) structure of A\selectlanguage{greek}β\selectlanguage{english}40 monomer reported on the
formation of a 3-10 helix spanning residues 13-23 at pH 7.3 at 50mM
NaCl.\textsuperscript{26} A\selectlanguage{greek}β\selectlanguage{english}42 monomer was found essentially disordered
but displays \selectlanguage{greek}α-\selectlanguage{english}helix spanning residues 15-24 and 29-35 in the presence
of micelles.\textsuperscript{7}

Small \selectlanguage{greek}β-\selectlanguage{english}strand contents were evidenced by circular dichroism (CD)
experiments\textsuperscript{17} and many simulations using atomistic or
coarse-grained models, suggesting notably the existence of multiple
transient \selectlanguage{greek}β-\selectlanguage{english}hairpin conformations covering the CHC and the C-terminus
(30-42),\textsuperscript{7,27,28} and revealing the very low
probabilities of the aggregation-prone N* states with U-shaped or
S-shaped fibrillar conformations.\textsuperscript{18}

\selectlanguage{greek}\textbf{2.2 Random Coil Oligomers with β-sheet content}\selectlanguage{english}

While small \selectlanguage{greek}α-\selectlanguage{english}helix and \selectlanguage{greek}β-\selectlanguage{english}strand contents are present in the spectrum of
conformations of A\selectlanguage{greek}β\selectlanguage{english}42, our current conformational view for small A\selectlanguage{greek}β\selectlanguage{english}42
oligomers is funneled toward \selectlanguage{greek}β-\selectlanguage{english}sheet conformations for several reasons.

The first reason comes from the high propensity of \selectlanguage{greek}β-\selectlanguage{english}sheets revealed by
oligomer simulations at a very high concentration of small fragments of
A\selectlanguage{greek}β \selectlanguage{english}(A\selectlanguage{greek}β\selectlanguage{english}16-22, A\selectlanguage{greek}β\selectlanguage{english}37-42, A\selectlanguage{greek}β\selectlanguage{english}25-35, A\selectlanguage{greek}β\selectlanguage{english}10-24 and A\selectlanguage{greek}β\selectlanguage{english}35-40), tau (PHF6 motif,
repeats R1-R4), transthyretin (105-115) and \selectlanguage{greek}β\selectlanguage{english}2-microglobulin (83-89)
peptides which also form fibrils.\textsuperscript{29-36} It is notable,
however, that two simulations on A\selectlanguage{greek}β\selectlanguage{english}16-22 oligomers proposed helical
intermediates.\textsuperscript{37-39}

Second, the preference for \selectlanguage{greek}β-\selectlanguage{english}sheet formation comes from the fact that
many computational methods do not explore the full conformational
ensemble. On-lattice Monte Carlo simulations do not allow the formation
of \selectlanguage{greek}α-\selectlanguage{english}helix oligomers\textsuperscript{40-42} and atomistic metadynamics
simulations do not include collective variables associated with side
chain packings of \selectlanguage{greek}α-\selectlanguage{english}rich oligomers. It is important to note that the
introduction of the steric zipper interface between the side chains as a
collective variable was found critical in metadynamics simulations to
understand the primary nucleation of 18 A\selectlanguage{greek}β\selectlanguage{english}37-42
peptides.\textsuperscript{35}

Additionally, off-lattice simplified models aimed at understanding
primary and second nucleation mechanisms either tune the probability of
the \selectlanguage{greek}β-\selectlanguage{english}strand monomer,\textsuperscript{43} or consider three states for
A\selectlanguage{greek}β \selectlanguage{english}dimers with coil-coil, coil-\selectlanguage{greek}β, \selectlanguage{english}and \selectlanguage{greek}β-β \selectlanguage{english}character to explain the
transition from amorphous to fibrils.\textsuperscript{44} These models
suggest that fibril formation at a concentration of mM can occur through
the assembly of early ordered oligomers, the assembly of nonfibrillar
aggregates rich in \selectlanguage{greek}β-\selectlanguage{english}sheet content, or the formation of amorphous
aggregates which reorganize to \selectlanguage{greek}β-\selectlanguage{english}sheet aggregates and to fibrils.

Beta-rich A\selectlanguage{greek}β\selectlanguage{english}42 oligomers ranging from elongated to compact shapes were
described by ss-NMR spectroscopy, ion mobility separation coupled to
mass spectrometry, and simulations, featuring multiple interfaces, mixed
parallel/antiparallel strands, perpendicular \selectlanguage{greek}β-\selectlanguage{english}sheets and
\selectlanguage{greek}β-\selectlanguage{english}barrels.\textsuperscript{6,7,11,28,45-49} For instance, atomistic
simulations in explicit solvent revealed \selectlanguage{greek}β-\selectlanguage{english}barrel motifs in A\selectlanguage{greek}β\selectlanguage{english}42 trimer
and tetramer.\textsuperscript{48,50,51} An hexamer peptide barrel was
found experimentally to be the building block of A\selectlanguage{greek}β
\selectlanguage{english}protofibrils.\textsuperscript{52}

Finally, using the multimer version of AlphaFold2,\textsuperscript{53}we
found that A\selectlanguage{greek}β\selectlanguage{english}42 dimers up to hexamers have a non-negligible probability
to display intramolecular \selectlanguage{greek}β-\selectlanguage{english}hairpin conformations spanning the CHC and
the C-terminus (residues 30-42), and in some cases to form
\selectlanguage{greek}β-\selectlanguage{english}barrels.\textsuperscript{54}

\textbf{2.3 Random coil Oligomers with alpha-helical content}

The AlphaFold2 machine-learning approach is based on protein data bank
(PDB) templates, sequence alignments, co-evolution rules and multiple
algorithms to design a protein-specific potential of mean force.
AlphaFold2 success stories include the prediction of single domain
protein structures,\textsuperscript{55} and most transmembrane protein
structures.\textsuperscript{56} AlphaFold2 limitations to predict very
accurately the structures of protein -- protein (peptide)
complexes\textsuperscript{57,58} and generate conformational
heterogeneity\textsuperscript{59} were reported.

At the date of the present study, the PDB contained about 200,000
structures.\textsuperscript{60} The most striking AlphaFold2 result for
the structures of A\selectlanguage{greek}β\selectlanguage{english}42 dimers up to hexamers is the prediction of
\selectlanguage{greek}α-\selectlanguage{english}helix topologies for all species in addition to \selectlanguage{greek}β-\selectlanguage{english}rich
topologies.\textsuperscript{54} The AlphaFold2 structures are shown in
Figure 1. While the dimer displays an antiparallel helix bundle spanning
the C-terminus (Figure 1A), all higher aggregates display parallel helix
bundles spanning the C-terminal residues 29-39. (Figures 1B-E). These
\selectlanguage{greek}α-\selectlanguage{english}rich oligomers are supported indirectly by numerous experiments on A\selectlanguage{greek}β
\selectlanguage{english}and many other amyloid polypeptides.

CD experiments on A\selectlanguage{greek}β\selectlanguage{english}42 and A\selectlanguage{greek}β\selectlanguage{english}40 peptides in pure buffer give 19\% and
32\% of \selectlanguage{greek}α-\selectlanguage{english}helix structure after 4 days of
incubation.\textsuperscript{61} Addition of trifluoroethanol suggested
\selectlanguage{greek}α-\selectlanguage{english}helical intermediates during A\selectlanguage{greek}β \selectlanguage{english}assembly,\textsuperscript{62} and
addition of low solvent polarity stabilized partial \selectlanguage{greek}α-\selectlanguage{english}helical structures
and accelerated A\selectlanguage{greek}β\selectlanguage{english}40 amyloid
fibrillation.\textsuperscript{63}Pyroglutamate-modified pEA\selectlanguage{greek}β\selectlanguage{english}(3-42)
aggregation also pointed to \selectlanguage{greek}α-\selectlanguage{english}helical intermediates, stabilized by
parallel C-terminus interactions, each monomer forming a
helix-turn-helix spanning residues 10-23 and 30-36.\textsuperscript{64}

Slow nucleation of short polyglutamine-containing Huntingtin fragments
via \selectlanguage{greek}α-\selectlanguage{english}helix-rich oligomers and inhibition of amyloid structure in a
Huntingtin fragment by targeting \selectlanguage{greek}α-\selectlanguage{english}helix-rich oligomers were also
reported experimentally.\textsuperscript{65,66} Using computational and
experimental approaches, human islet amyloid polypeptide (hIAPP)
fragment 8-20 fibril formation starts from isolated helical monomers,
helical dimers to hexamers, followed by the conversion to \selectlanguage{greek}β \selectlanguage{english}at the
hexamer level.\textsuperscript{67} PolyQ-A\selectlanguage{greek}β\selectlanguage{english}30-42 peptides at \selectlanguage{greek}µ\selectlanguage{english}M
concentration suggested an aggregation triggered by a rapid formation of
\selectlanguage{greek}α-\selectlanguage{english}helical oligomers mediated by the C-terminal residues, as assessed by
CD and FTIR (Fourier Transformed Infrared)
spectroscopies.\textsuperscript{68} Infrared nanospectrometry monitored
a \selectlanguage{greek}α-\selectlanguage{english}to-\selectlanguage{greek}β \selectlanguage{english}transition during the self-assembly of the N-terminal Josephin
domain of ataxin 3.\textsuperscript{69} The conversion of rationally
designed \selectlanguage{greek}α-\selectlanguage{english}helical peptides to amyloid fibrils and the oligomerization
of natural hexapeptides into amyloid fibrils through \selectlanguage{greek}α-\selectlanguage{english}helical oligomers
are also well established.\textsuperscript{70,71} Overall, there are
many experiments reporting a minor population of partially folded
helical oligomers during amyloid fibril
formation.\textsuperscript{72,73}

Additionally, a rational design of \selectlanguage{greek}α-\selectlanguage{english}helical peptide inhibitors
targeting A\selectlanguage{greek}β\selectlanguage{english}40 surface reduces the generation of toxic A\selectlanguage{greek}β \selectlanguage{english}toxic
oligomers.\textsuperscript{74} Helical peptide foldamers and
peptidometics were found dual inhibitors of A\selectlanguage{greek}β \selectlanguage{english}and hIAPP
fibrillization.\textsuperscript{75} Alpha-helix mimetics, which induce
\selectlanguage{greek}α-\selectlanguage{english}helicity in A\selectlanguage{greek}β \selectlanguage{english}using NMR and CD, inhibit the seed-catalyzed
aggregation of A\selectlanguage{greek}β.\selectlanguage{english}\textsuperscript{76} Based on ion mobility
spectrometry -- mass spectrometry combined to MD simulations, it was
suggested that A\selectlanguage{greek}β \selectlanguage{english}C-terminal interactions play a key role in their
inhibitory activity.\textsuperscript{77} Finally, it was found that
A\selectlanguage{greek}β\selectlanguage{english}25-35 peptide forms early stage helical conformations by CD and Raman
spectroscopic techniques, and carvedilol inhibits A\selectlanguage{greek}β\selectlanguage{english}25-35
fibrillation.\textsuperscript{78}

Computationally, AlphaFold2 \selectlanguage{greek}α-\selectlanguage{english}helical tetramer and hexamer structures
are very stable using CHARMM36m-TIP3P modified and AMBER99SB-DISP for
0.3 \selectlanguage{greek}µ\selectlanguage{english}s MD simulations at 310 K.\textsuperscript{54} Transient formation
of helical conformations differing from helix bundles was reported by
numerous simulations of A\selectlanguage{greek}β\selectlanguage{english}40 and A\selectlanguage{greek}β\selectlanguage{english}42
oligomers,\textsuperscript{7,28,46,79} but a recent simulation proposed
that conformations with \selectlanguage{greek}α-\selectlanguage{english}helical structure have a high propensity to
initiate A\selectlanguage{greek}β\selectlanguage{english}42 aggregation.\textsuperscript{80} Finally, it should be
noted that the helix propensity of amyloid peptides is a fundamental
requirement to fulfill the lipid-chaperon model,\textsuperscript{81} and
helical intermediates during amyloid formation are catalysed by
membranes.\textsuperscript{36,72}

\textbf{3. Conclusions}

The A\selectlanguage{greek}β\selectlanguage{english}42 monomer and oligomer structures in aqueous solution are of high
importance as they initiate fibril formation and are believed to be the
most toxic species. While the community believes on random coil --
\selectlanguage{greek}β-\selectlanguage{english}sheet oligomers and the role of \selectlanguage{greek}β-\selectlanguage{english}hairpin\textsuperscript{82} in the
early steps of aggregation, the existence of \selectlanguage{greek}α-\selectlanguage{english}helical bundle metastable
intermediates of A\selectlanguage{greek}β\selectlanguage{english}42 oligomers is rarely cited, while it is predicted
by AlphaFold2 and is, more importantly, supported indirectly by a large
number of experimental studies on A\selectlanguage{greek}β \selectlanguage{english}and many amyloid polypeptides under
various conditions. It is important to note that there is a general
resistance of the field to believing CD in detecting \selectlanguage{greek}α-\selectlanguage{english}helix in
aggregates, because of light-scattering interference and skewing of the
CD spectrum. ~But the \selectlanguage{greek}α-\selectlanguage{english}helix signal in oligomers was further evidenced
by FTIR and Raman spectroscopies in addition to CD.~ Clearly, the
coexistence of \selectlanguage{greek}α-\selectlanguage{english}rich oligomers and \selectlanguage{greek}β-\selectlanguage{english}rich oligomers en route to fibril
formation has to be considered when designing drugs targeting A\selectlanguage{greek}β
\selectlanguage{english}monomers and oligomers.\textsuperscript{76,81,83,84}

AUTHOR INFORMATION

Corresponding Author

E-mail: philippe.derreumaux@ibpc.fr

ORCID:

Derreumaux: 0000-0001-9110-5585

Sterpone: 0000-0003-0894-8069, fabio.sterpone@ibpc.fr

Nguyen: 0000-0003-1284-967X, Phuong.nguyen@ibpc.fr

Notes. The authors declare no competing financial interest.

ACKNOWLEDGMENTS

This work was supported by the ``Initiative d'Excellence'' program from
the French State, Grant ``DYNAMO'', ANR-11-LABX-0011. PD thanks Ronald
Wetzel for useful discussions and Geoffrey Letessier of the Laboratoire
de Biochimie Th\selectlanguage{ngerman}éorique for technical support.

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\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1.} Representative structures of AlphaFold2 structures of
A\selectlanguage{greek}β\selectlanguage{english}42 aggregates. (A) dimer, (B) trimer, (C) tetramer, (D) pentamer and
(E) hexamer showing the interface made by the C-terminus in helical
conformations.\textsuperscript{54}

\selectlanguage{english}
\FloatBarrier
\end{document}

