Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion

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Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion in Small Amyloid Forming Peptide under Nanoconfinement Sathish Kumar Mudedla, N. Arul Murugan, and Hans Ågren J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b07917 • Publication Date (Web): 25 Sep 2018 Downloaded from http://pubs.acs.org on September 26, 2018

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The Journal of Physical Chemistry

Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion in Small Amyloid Forming Peptide under Nanoconfinement Sathish Kumar Mudedla,a,* N. Arul Murugana,* and Hans Agrena,b a

Division of Theoretical Chemistry and Biology, School of Biotechnology, AlbaNova University Center, Royal Institute of Technology (KTH), S-106 91 Stockholm, Sweden b Department of Physics and Astronomy, Uppsala University, Box 516, SE-751 20 Uppsala, Sweden. * To whom correspondence should be addressed. E–mail: [email protected], [email protected] Abstract Understanding the mechanism of fibrillization of amyloid forming peptides could be useful for the development of therapeutics for Alzheimer disease (AD). Taking this standpoint, we have explored in this work the free energy profile for the inter-conversion of monomeric and dimeric forms of amyloid forming peptides into different secondary structures namely betasheet, helix and random coil in aqueous solution using umbrella sampling simulations and density functional theory calculations. We show that the helical structures of amyloid peptides can form beta sheet rich aggregates through random coil conformations in aqueous condition. Recent experiments (Chem. Eur.J. 2018, 24, 3397-3402 and ACS Appl. Mater. Interfaces, 2017, 9, 21116–21123) show that Molybdenum disulphide nanosurface and nanoparticles can reduce the fibrillization process of amyloid beta peptides. We have unravelled the free energy profile for the inter-conversion of helical forms of amyloid forming peptides into beta-sheet and random coil in the presence of a two dimensional nanosurface of (MoS2). Results indicate that the monomer and dimeric forms of the peptides adopt the random coil conformation in the presence of MoS2 while the helical form is preferable for the monomeric form and that the beta-sheet and helix forms are the preferable forms for dimers in aqueous solution. This is due to strong interaction with MoS2 and intramolecular hydrogen bonds of random coil conformation. The stabilization of random coil conformation does not lead to beta sheet like secondary structure for aggregate. Thus the confinement of MoS2 promotes deaggregation of amyloid beta peptides rather than aggregation, something that could be useful for the development of therapeutics for AD.

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Introduction The fibrillization of biomolecules such as Amyloid β, tau, prion, alpha-synuclein proteins causes many neurodegenerative disorders such as Alzheimer's, Huntington's and Parkinson's diseases.1-3 The fibrillization process involves aggregation of soluble monomers into beta sheet rich dimers, trimers, oligomers, protofibrils and matured insoluble plaques.4 The toxicity of an amyloid peptide is mainly due to the formation of aggregates in the form of oligomers.5,

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intermediate sized

It is found that the oligomers of amyloid beta of

length 1-42 are toxic rather than the large fibrils. The possibility to inhibit amyloid aggregation and busting and clearance of fibrils could therefore have great implications for the development therapeutics in treatment of various neurodegenerative diseases. The stabilization of native structures and subsequent prevention of conformational changes required for aggregation process is also a possible way to treat neurodegenerative diseases. The most direct way to treat the neurodegenerative diseases is to inhibit the production of amyloid peptides and to bust the fibrils that are already formed in the brain. In recent years many small molecules are used to inhibit the fibrillization process and also to bust the matured fibrils.7-15 The green tea polyphenol molecule inhibits the amyloid aggregation through the stabilization of unfolded structures of amyloid beta peptides.16 Several nanomaterials have been shown to be suitable for applications in amyloid fibril inhibition and disintegration of matured fibrils. Nanomaterials made of polymers, gold nanoparticles, carbon nanomaterials and selenium nanoparticles have been applied to inhibit amyloid aggregation.17-24 For example, gold nanoparticles have been used as photothermal busting agent for amyloid fibrils24 and functionalized gold nanoclusters have been proposed as inhibitors for the amyloid forming protein.25 Carbon based nanomaterials such as fullerenes, 2


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carbon nanotubes, graphene and graphene oxide have been tested as well and have shown some promises for inhibition and busting of amyloid fibrils.26-28 Amyloid peptides form nonamyloid aggregates in the presence of carbon nanotube.28 Graphene acts as busting agent for the amyloid fibrils by forming stable aromatic π-π stacking interactions with phenylalanine residue as confirmed by experimental and molecular simulation studies.29 Graphene oxide can also be used for disintegration and clearing of amyloid aggregates29,30 and further has shown to act as modulator for amyloidosis.31,32 Experimental reports have shown that twodimensional materials such as Tungsten disulphide (WS2) can have inhibitory effects on the fibrillization of amyloid peptides.33,34 In addition, Molybdenum disulphide (MoS2) has been used in many applications in tissue engineering and biomedicine.35,36 It has indeed been proved that MoS2 based nanoparticles can be applied as multifunctional inhibitors (for both busting and inhibition of aggregation process) for Alzheimer's disease.37 Recently, experiments show that an MoS2 surface also can modulate the fibrillization of amyloid and amylin peptides.38 In these experiments, the hydrophobic fragment of an amyloid peptide (sequence from 33-42) was used to study the modulation effect on the fibrillization, something that could be attributed to the ability of MoS2 to reduce the beta sheet contents of the amyloid peptides in the fibrils. The understanding of the deaggregation process in the presence of MoS2 surface at atomic scale would be useful to expand its applications in the treatment of neurodegenerative diseases. This has motivated us to investigate the transition of amyloid peptides from beta sheet to helix and random coil conformations using umbrella sampling molecular dynamics simulations and by further computing the relative stabilities of different secondary structures along the aggregation pathway using density functional theory calculations.

In order to

understand the MoS2 surface induced deaggregation, the free energy profile for alpha-helix 3



to beta-sheet interconversion process has been studied alone as well as in presence of surface.

Computational Details Many studies have used the fragment (33-42) from amyloid beta peptide as a model peptide to understand the structure of amyloid fibrils and aggregation process.39-41 The input structures of monomer and dimer of amyloid peptides (33-42) with sequence (GLMVGGVVIA) have been extracted from protofibril (pdb id: 2BEG).42 In a traditional way to avoid the charge accumulation in the terminals, the ends of the peptides were capped with acetyl and N-methyl groups. Three sets of calculations were carried out to understand the MoS2 nanosurface induced changes in the monomeric and dimeric forms of this amyloid peptide: (i) monomer of amyloid peptide in aqueous solution (ii) dimer of amyloid peptide in aqueous solution (iii) monomer and dimer of amyloid peptides on MoS2 surface. The first two sets of simulations were carried out to study the structure of these peptides in aqueous condition. For the dimer we have only considered a parallel conformation as it is in the protofibril structure. A two-dimensional MoS2 nanosurface with 89.3 and 79.3 Å dimensions was considered as a model to understand the influence of the surface on the fibrillization of amyloid peptides. The peptides were placed parallel to each other above the surface of MoS2 at a distance of 9.4 Å. Molecular dynamics simulations were performed for the complexes of MoS2 with amyloid peptides using the GROMACS-4.6.5 package.43-45 The force field parameters for the MoS2 surface were taken from previous studies.46, 47 The charges 0.76 and -0.38 were used for molybdenum and sulphur atoms respectively. Amber99sb force field parameters were used for the peptides. The peptides and their complexes with MoS2 surface were solvated in a orthorhombic box with TIP3P water model. The periodic boundary 4


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conditions were applied in all directions. The interactions between MoS2 and its mirror image were frozen during the simulation. The structures in solution were relaxed by energy minimization using the steepest decent method. Subsequently the minimized structures were equilibrated at 298 K and 1 bar pressure for 1 ns by imposing position restraints on the structures. Temperature and pressure were controlled using the velocity rescaling and Parrinello-Rahman algorithms.48-50 Further, the structures were relaxed for 1 ns using 2 fs as time step in the NPT ensemble. During the simulation, the position of the MoS2 surface was restrained using harmonic potentials. The electrostatic interactions were calculated using the Particle Mesh Ewald method and bonds between hydrogen and heavy atoms were constrained with the help of the LINCS algorithm.51, 52 The sampling of potential energy surface which has regions separated with larger energy barrier is difficult using classical molecular dynamics simulations. Umbrella sampling is the routinely used technique to study such systems with basins separated by kinetic barriers. This can sample the states which cannot be done by unbiased classical molecular dynamics simulations. The calculation of free energy difference between two states with larger kinetic barrier is very difficult with unbiased simulations whereas umbrella sampling simulations can provide free energy change along a reaction coordinate. The structures obtained from molecular dynamics simulations were used as initial configuration for the subsequent umbrella sampling simulations. A previous study has proven that the average psi angle can be used as a reaction coordinate in umbrella sampling simulations to facilitate the transition from helix to beta sheet conformation.53 The authors also compared the results with other reaction coordinates such as radius of gyration and number of native contacts and the use of three reaction coordinates arrives to similar results. Hence, in this study, we have only considered the average psi angle as a reaction coordinate to convert the beta sheet structure to 5



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helix conformation. In the case of monomeric form of the peptide, there are 8 different psi angles (correspondinging to each peptide bond) and we constrain each of these psi angles to certain value so that the average psi angle takes this value. The average psi angle of one monomer is 140˚ in the starting conformation and the average angle was increased to 180˚ with an increment of 10˚ and decreased to -180˚ with an increment of

-10˚ . We have

overall 37 independent simulations corresponding to each of this angle and simulations were performed for 10 ns on each window (a total of 370 ns for monomeric system). Input configuration for each simulation has been chosen from the final configuration of the previous simulation to achieve equilibration quickly. Each configuration was restrained using a harmonic spring constant of 150 kJ.mol-1.rad-2. All umbrella sampling simulations were performed using the PLUMED-2.0 package.54 The data received from the umbrella sampling simulation was used to calculate the free energy by employing weighted histogram analysis method.55 A similar protocol has been followed for obtaining the free energy profile for the dimeric form of the peptide in aqueous solution as well as on the surface of MoS2 . Only difference is that the number of constraints for the dimeric form is now 16 instead of 8 as in monomeric form. The dictionary of protein secondary structure (DSSP) tool which recognizes the hydrogen bond patterns and geometrical features has been used to investigate the secondary structure of the peptide in monomeric and dimeric form.56 To further validate the free energy profiles as obtained from the force-field methods, we have also carried out calculations using density functional theory for configurations along the free energy profiles for both the cases of monomer and dimer in aqueous solution. We have collected 10 configurations from the last 5 ns of simulations for each of the selected 17 psi angles to perform single point calculations. These calculations were carried out in aqueous solution with polarizable continuum model for solvent description. The plots of average 6


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energy value for various configurations corresponding to different psi angles are shown in Figures 2 and 4 for monomer and dimer respectively. Previous studies have shown that the M06-2X functional is suitable for the investigation of noncovalent interactions in the systerms of similar kind as studied here.57,

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Hence, in this study we have calculated the

single point energies at M06-2X/6-31G* level of theory with the help of the Gaussian16 software.59 These sets of calculations were carried out in water described using SMD solvent model which includes the electrostatic interaction between the solvent and solute electron density along with dispersion and cavitation contributions.60 The interaction energy between two monomers was calculated using a supermolecule approach and was corrected for basis set superposition error using the counterpoise method.61 Results and Discussion Initially, when the equilibrated monomer structure is relaxed for 1 ns in aqueous solution it attains the random coil conformation. In this form, the average of the psi angles is around 140˚. The same conformation has been used as starting point for the umbrella sampling simulations. We used the backbone psi angles of the amyloid peptide (33-42) as reaction coordinates to sample its different conformations and these dihedral angles varied from -180˚ to 180˚. The calculated free energy values with respect to the psi angle for the monomer are given in Figure 1 (along with the representative structures corresponding to each minima). The free energy profile has two minima separated with energy barriers. To understand the structural changes throughout the free energy surface, the calculated secondary structural elements for each average psi angle are given in Table 1. It can be noted that the helix formation occurs at average psi values from -20 to -60. The coil, bend and turn -like secondary structures are dominant for monomeric peptide having other psi angles. The lowest minimum is located at the average psi angle around -40˚. At this point, 35% of the peptide 7



exists in the helical conformation (refer to representation conformation shown in Figure 1), while the random coil structure is prominent for the angles around 160˚. The monomer is more stable in the helical form when compared to random coil structure - the two conformational forms are separated with a barrier of around 7.4 kcal/mol. The transition from helix to coil needs to cross this energy barrier, while for coil to helix the barrier is much smaller, around 3.4 kcal/mol. So we have observed that the conversion of coil to helix in restraint free molecular dynamics simulation within time scale of 50 ns and that the monomer persists in the helical conformation in solution. We have not found the stabilization of linear conformation (the structure involved in the formation of beta sheet-like secondary structure) in the monomer state. In the case of monomer, the stability of the secondary structural elements is only due to the intra-molecular hydrogen bonds. The average number of hydrogen bonds is non-zero only for the 1st minimum (5 in number). The helix form is the most stable minimum, something that can be referred to its large number of intra-molecular hydrogen bonds and that the increase in intra-molecular hydrogen bonds favours the transition from random coil to helix in the monomer. Further, to validate the free energy calculation the stability of the obtained conformations from umbrella sampling simulations were subjected to density functional theory calculations. Density functional theory methods are significantly useful for structure prediction of molecules, simulation of chemical reactions and calculations of thermodynamic properties with better accuracy than force-field methods. Dispersion corrected density functional theory methods accurately describe the non-covalent interactions such as hydrogen bonds, π-π stacking, cation-π, anion-π, CH-π, NH-π and CO-π.57,

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The amyloid beta peptides form

dimer with the help of non-covalent interactions. Therefore, in this study, to ensure the results obtained from umbrella sampling simulations we calculated the energetics using dispersion 8


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corrected density functional theory methods. The calculated relative energies in aqueous phase are shown in Figure 2. The energy profile also shows two minima at average psi -40 and 160° as similar to free energy profile obtained through WHAM analysis. The average energy values indicate that the helical form is more stable when compared to the coiled structure. The helix is stabilized by 32.9 kcal/mol compared to the coiled conformation. The value of the energy barrier is high when compared to WHAM analysis but the trend in energetics remains the same. These results are in close agreement with the results of the umbrella sampling simulations and thus sustain the reliability of the free energy calculations using the above described force-field methods. Dimerization of the amyloid peptide has been investigated by considering the dimer which is taken from the crystal structure of the protofibril as starting structure. The extracted dimer was relaxed for 1 ns in solution during which the structure remains in dimeric form. The interconversion from beta sheet to helix and random coil conformations is noted by restraining the average psi angles of the peptide over the range 180° to -180°. The calculated free energies for the transitions between these conformations are shown in Figure 3 (along with the representative structures corresponding to each minimum and maximum). The calculated secondary structure elements for the conformations at all average psi angles are presented in Table 2. It can be seen that beta sheet structures are observed at average psi angles from 100 to 140˚ and that the percentage of beta sheet ranges from 45 to 60 %. The remaining residues are present in the coiled conformation. The beta sheet structure disappears on further decrease in the average psi angle after 100˚ and the peptide is enriched with coillike conformation until 40˚. The formation of helix and 310 helix occurs at -10˚. The dimeric peptide attains predominant helical conformation at -40˚ and the population of helix secondary structure further decreases with the lowering of average psi values beyond this 9



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value. The structures that correspond to the minima and maximum on the free energy surface are dimers of helix, beta sheet and random coil structures. At -40˚, individually each peptides of dimer achieve a stable helical conformation (refer to Figure 3). A second minimum occurs between 110˚ and 140˚ and these conformations correspond to the beta sheet form. As can be seen from Figure 3, the helical form and beta sheet forms are separated with random coil structures and the energy barrier is 2.7 kcal/mol. We noted from Figure 3 that the stable random coil structures appear at the average psi of 50˚. Similar to this outcome, a recent work on amyloid peptides of Huntington’s protein reports on the existence of random coil structures along the interconversion of helix to beta sheet conformations.53 The helix and beta sheet forms are more stable when compared to the random coil structure. Further, to understand the stability of the minima on free energy surface, we calculated the number of contacts between the two monomers within 4 Å and the values are 178, and 417 at the minima 1 and 2, respectively. These minima are stabilized by 0 and 8 inter-molecular hydrogen bonds. The number of contacts and intermolecular hydrogen bonds are thus high for the dimer in the beta sheet form compared to the other forms. However, as we discussed earlier, the helical conformations in the monomeric peptide are more stable due to the intramolecular hydrogen bonds. Our results show that the

peptides in helical structure

convert to beta sheet like secondary structure by adopting intermediate random coil conformation. The secondary structure of peptides is crucial for the involvement in aggregation process. Hence, the results provide an insight that the stabilization of random coil structures could be a possible way to inhibit aggregation processes of amyloid peptides. To quantify the stability of all conformations, DFT calculations were performed for the calculation of interaction energies using the counterpoise method at the M06-2X/6-31G* level of theory. The calculated relative energies are given in Figure 4 and it can be clearly 10


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seen that minima for helical conformation and beta sheet form occur at -40 and 120˚, respectively. Interestingly, the helical conformation is still more stable than that of beta sheet conformation for the dimeric peptides. When the peptide size grows to bigger oligomer, the relative stability of these two secondary structures may change leading to growth of the fibrils spontaneously. The minimum at 120˚ can be attributed to a high percentage of beta sheet conformation which can be seen from secondary structure analysis (Table 2). Also the Table shows that the helical conformation and beta sheet forms are separated with random coil structures. The position of maximum on the free energy surface from umbrella sampling simulations is different from the maximum in the energy profile as obtained from density functional theory calculations and in particular in the latter case the position of maximum is shifted to larger average psi value. The calculated interaction energies, shown in Figure 5, correspond to the conversion from helical dimer to beta sheet form. The interaction energy is the least when the two peptides are in the helix conformation and it increases with the loss of helical conformation and becomes high for the beta sheet form. It is worth noticing that the interaction energy for the peptides in the random coil structures is larger when compared to helical form, which become stabilized through intermolecular interactions rather than by intramolecular hydrogen bonds which are dominant in the case of helix. The helical dimer is stabilized through dispersion interactions whereas hydrogen bond interactions are predominant in the case of beta sheet structure. The intermolecular hydrogen bonding interactions is the driving force for the formation of beta sheet conformations. Instead of comparing the intermolecular energy alone, if we compare the total energy (which is a sum of intramolecular and intermolecular energies), dimer with helical conformation is more stable than the dimer in beta sheet form. However the increase in number of monomers may lead to change in their relative stabilities.

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Previous studies have shown that MoS2 surfaces can change the conformation of the peptide after adsorption, something that motivates us to explore the interaction of the amyloid peptide with a two dimensional surface of MoS2 in order to understand the transition of random coil to helical conformation when compared to solution. We find, that the interconversion from random coil to helix for the monomeric peptide on MoS2 surface is not similar to the case of monomer in solution. The calculated secondary structure details are given in Table 3. It can be noted that there is no formation of α-helical conformation as we observed in the case of aqueous solution the reason being that these structures are destabilized on the MoS2 surface. Despite of the α-helix, the monomer adopts to a 310 helix in the presence of the MoS2 surface at average psi of -20˚. At this point, monomer has 26 percentage of 310 helix and the remaining residues are present in coil, bend and turn conformations. Except for -20˚, these secondary structural elements are prominent conformations for the monomer and occur at all average psi values in the presence of the MoS2 surface. The calculated free energy profile, with three minima and the representative conformations for each minimum, is shown in Figure 6. Here we see contrasting results when compared to the monomer free energy landscape in aqueous solution. Interestingly, the lowest minimum is found between 60˚ and 70˚ and the corresponding conformation is random coil. The other minima, around at -120 and -160˚, correspond predominantly to coil and turn conformations. Even though the peptide achieves psi angles necessary to form helix conformation, the interaction with the MoS2 surface does not allow it be in helical form. MoS2 thus stabilizes the coil or disordered conformations. The average interaction energies (over the 10 ns data) between the peptide and the MoS2 surface were calculated for all conformations corresponding to average psi angles in the range -180 to 180 and shown in Figure 7. It shows the variation in the interaction energy with respect to the average psi angle and the contributions of van der Waals and electrostatic interactions. It is clearly noted that interaction energies are high for 12


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the angles from 50˚ to 80˚. This attributes to the high stability of random coil structures on the surface of MoS2. It can be seen from Figure 7, that the interaction of the peptide with MoS2 is predominantly stabilized by the van der Waals interaction rather than by electrostatic contributions. In the random coil conformation, the backbone atoms are exposed and can therefore easily interact with the MoS2 surface. The backbone atoms and side chains of the peptide involve in van der Waals interactions with sulphur atoms of the MoS2 surface. The calculated average number of intra-molecular hydrogen bonds in the peptide is shown in Figure 8. It can be seen that the random coil conformation also is stabilized to some extend by intra-molecular hydrogen bonds similarly to the helical form. The number hydrogen bonds are comparatively large for the structures corresponding to average psi angles -40˚, -50˚, 50˚ and 60˚. The high interaction energy with MoS2 and the intra-molecular hydrogen bonds of monomer explain the high stability of the random coil conformation for amyloid beta peptide on the surface of MoS2. The surface interaction does thus not trigger the peptide to form a helical conformation and the random coil conformation thus remains stabilized on the surface. Further, to understand the conformational behaviour of dimer on interaction with MoS2 surface, the dimer form of the peptide, which is in the beta sheet conformation, was allowed to relax for 1 ns on the surface of MoS2. It was found that the structure of the dimer changes upon adsorption onto the surface of MoS2 and that few of the amino acids attain coil-like structures. The dimer obtained 32, 61 and 2 % of beta sheet, coil and bend conformations, respectively. In aqueous solution, the same dimer has 47% of beta sheet content after the simulation of 1 ns. The loss of beta sheet conformation can thus clearly be attributed to the interaction with the MoS2 surface. This final structure from this simulation has been used as the input structure for calculating the free energy landscape for interconversion from beta 13



sheet to helix conformation on MoS2 surface. The calculated secondary structure elements as a function of average psi angles are presented in Table 4. Interestingly, beta sheet conformations (to an extend of 26 %) are observed only for 140˚. Other than this case for remaining psi angles, the dimer did not attain beta sheet structures due to the interaction with the MoS2 surface. This shows that MoS2 induces the conformational changes in beta sheet structures upon interaction. The dimer peptides adopt the secondary structures - coil, bend, turn and 310 helix - similarly to monomer peptides on the surface of MoS2. The calculated free energy profile is shown in Figure 9. The free energy profile for the transition of beta sheet to helical and random coil conformation on the surface of MoS2 has three minima and the lowest minimum occurs around at 60˚. At this minimum, the monomers are neither in helical or beta sheet-like but in the random coil conformation as can be noted from Table 4. The dimer exists in random coil structure similar to the monomer peptide on the surface of MoS2. Furthermore, the number of intramolecular hydrogen bonds within the two monomers on MoS2 surface is as high as 10 which can be compared with the number of intermolecular hydrogen bonds (8) between dimers in aqueous solution. Therefore, in addition to the internal stability of the monomers, the interaction between MoS2 and monomers further stabilizes the random coil conformations in the dimeric peptides. Thus, MoS2 can inhibit the transition of amyloid beta peptides from coil to beta sheet like structures by stabilizing the random coil structures. The recent experimental study presented in Ref 38 shows that the MoS2 surface can inhibit the fibrillation of amyloid peptides and proves the reduction in beta sheet content of amyloid peptides (33-42) in fibrils using circular dichrosim spectra. Our results are well in agreement with the previous experimental study (Ref 38). As the aggregation of amyloid peptides into oligomers and then to fibrils is the pathogenic mechanism behind Alzheimer’s disease the results confirm that the MoS2 surface could be useful for the inhibition of fibrillization process in this disease. The practical use of MoS2 2D materials for therapeutic 14


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applications may be questionable as they have to be carried to the brain through cell membranes and blood brain barriers. However, one can design molecular analogues with properties similar to that of 2D MoS2, and understanding the microscopic mechanism behind the surface induced changes in the dimerization dynamics is then needed. We believe that the current simulations can contribute to such insight.

Conclusions Free energies associated with the transition of the beta sheet form to helical and random coil conformations of small amyloid forming peptides have been investigated using molecular dynamics simulations with umbrella sampling method and density functional theory calculations. It is found that in aqueous solution monomeric form prefers to exist in helical structure and in their dimeric form or in higher oligomeric form they can convert to beta sheet like secondary structures through random coil structures. The helix and beta conformations are thus more stable forms for amyloid beta in aqueous solution. However, the relative energetics of different secondary structures for monomer and dimer are altered on interaction with an MoS2 surface. Rather a coil-like secondary structure appears to be the most stable one for both monomeric and dimeric peptides. The disordered or random coil conformations are more stable due to the high interaction energy with the surface (dominated by electrostatic interactions) and intra-molecular hydrogen bonds within the monomer. The surface stabilizes the random coil conformation, which is an intermediate structure along the alpha-helix to beta-sheet interconversion pathway and further prevents beta-sheet rich aggregate formation as occurring in aqueous solution. The results provide molecular level insight into the recent 15



experimental findings that molybdenum disulphide nanosurfaces can reduce the fibrillization process of amyloid beta peptides. The stabilization of disordered conformations of amyloid beta peptide is here similar to the inhibition mechanism of green tea polyphenol molecule. Hence, this supports the contention that MoS2 surfaces can be exploited for the development of nanomaterials based therapeutics for the treatment of Alzheimer disease. Supporting Information The time evolution of average psi for the minimum energy structures is given in Figure S1 to Figure S4. Acknowledgements The authors acknowledge support from the Swedish Foundation for Strategic Research (SSF) through the project “New imaging biomarkers in early diagnosis and treatment of Alzheimer’s disease” and the support from SLL through the project “Biomolecular pro-filing for early diagnosis of Alzheimer’s disease”. This work was supported by the grants from the Swedish Infrastructure Committee (SNIC) for the projects “Multiphysics Modeling of Molecular Materials” (SNIC2017-12-49) and “In-silico Diagnostic Probes Design” (SNIC2018-3-3).

References 1. Wisniewski, T.; Ghiso, J.; Frangione, B. Biology of A Beta Amyloid in Alzheimer's Disease. Neurobiol. Dis. 1997, 4, 313–328. 2. Ross, C. A.; Tabrizi, S. J. Huntington's Disease: From Molecular Pathogenesis to Clinical Treatment. Lancet Neurol. 2011, 10, 83–98. 3. Irvine, G. B.; El-Agnaf, O. M.; Shankar, G. M.; Walsh, D. M. Protein Aggregation in the Brain: The Molecular Basis for Alzheimer's and Parkinson's Diseases. Mol. Med. 2008, 14, 451–464. 4. Hardy, J.; Selkoe, D. J. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics. Science 2002, 297, 353-356. 5. Sultana, R.; Butterfield, D. A. Alterations of Some Membrane Transport Proteins in Alzheimer's Disease: Role of Amyloid β-peptide. Mol Biosyst. 2008, 4, 36‐41. 6. Kang, J.; Lemaire, H. G.; Unterbeck, A.; Salbaum, J. M.; Masters, C. L.; Grzeschik, K. H.; Multhaup, G.; Beyreuther, K.; Müller-Hill, B. The Precursor of Alzheimer's 16


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Table 1: Secondary Structure Elements of Monomer in Aqueous Solution

Average Psi Coil Bend Turn α-Helix 310-Helix 5-Helix 180 160 140 120 100 80 70 60 50 40 20 10 -10 -20 -30 -40 -60 -80 -100

0.9 0.95 0.94 0.97 0.88 0.86 0.81 0.83 0.83 0.78 0.48 0.31 0.32 0.33 0.31 0.3 0.3 0.5 0.67

0.1 0.05 0.06 0.03 0.12 0.13 0.17 0.16 0.16 0.18 0.18 0.07 0.12 0.09 0.06 0.01 0.18 0.19

0.48

0.01 0.02 0.02 0.04 0.34 0.61 0.48 0.44 0.41 0.34 0.31 0.31 0.04

0.03 0.17 0.35 0.39

0.01 0.01 0.08 0.11 0.04

21


β-Sheet β-Bridge


Page 22 of 33

Table 2: Secondary Structure Elements of Dimer in Aqueous Solution

Average Psi Coil Bend Turn α-Helix 310-Helix 5-Helix

β-Sheet β-Bridge

180 160 140 120 100 80 70 60 50 40 20 10 -10 -20 -30 -40 -60 -80 -100

0.06 0.19 0.45 0.54 0.6 0.34 0.05 0.02

0.83 0.74 0.49 0.49 0.35 0.58 0.86 0.92 0.94 0.88 0.49 0.35 0.23 0.24 0.23 0.21 0.2 0.19 0.53

0.01 0.01 0.01

0.12 0.09 0.02 0.04 0.03 0.01

0.39

0.03 0.33 0.45 0.29 0.31 0.19 0.11 0.08 0.02 0.03

0.11 0.18 0.47 0.61 0.25 0.02

0.01 0.06 0.3 0.19 0.04

0.02 0.43 0.72 0.01

22


0.05 0.02

0.03 0.04 0.01 0.01 0.01

Page 23 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3: Secondary Structure Elements of Monomer in the Presence of MoS2 Surface

Average Psi Coil Bend Turn α-Helix 310-Helix 5-Helix 180 160 140 120 100 80 70 60 50 40 20 10 -10 -20 -30 -40 -60 -80 -100

0.99 1 0.94 0.78 0.8 0.81 0.80 0.80 0.80 0.79 0.8 0.76 0.57 0.46 0.23 0.2 0.30 0.61 0.74

β-Sheet β-Bridge

0.01 0.06 0.22 0.2 0.06

0.01

0.13 0.13 0.06 0.10 0.38 0.26

0.20 0.20 0.20 0.20 0.20 0.24 0.21 0.16 0.60 0.79 0.59 0.01

0.09 0.26 0.11

Table 4: Secondary Structure Elements of Dimer in the Presence of MoS2 Surface Average Psi Coil Bend Turn α-Helix 310-Helix 5-Helix

180 160 140 120 100 80 70 60 50 40 20 10 -10 -20 -30 -40 -60 -80 -100

0.95 0.95 0.68 0.84 0.95 0.93 0.89 0.86 0.86 0.86 0.88 0.67 0.42 0.44 0.42 0.46 0.7 0.76 0.80

0.01

0.02 0.01

0.02 0.08 0.05 0.05 0.05 0.04 0.05 0.09 0.10

β-Sheet β-Bridge

0.26 0.03 0.02 0.04 0.08 0.09 0.09 0.05 0.16 0.18 0.23 0.32 0.32 0.19 0.11 0.05

0.05 0.29 0.24 0.17 0.14 0.05

23


0.08


8 7 6

Free Energy(kcal/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 24 of 33

5 4

2

3 2 1 0

1 -1 -200

-150

-100

-50

0

50

100

150

Average Psi(°)

1

2

Figure 1: Free energy profile of various conformations of monomer.

24


200

Page 25 of 33

50

Relative Energy(kcal/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


40

30

20

10

0 -100

-50

0

50

100

150

200

Average Psi(°) Figure 2: The calculated relative energies of conformations at different psi angles using M062X/6-31G* level of theory.

25



5

4


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 33

3

2

2 1

0

1 -200

-150

-100

-50

0

50

100

150

200

Average Psi(°)

2

1

Figure 3: Free energy for the transformation of beta sheet to helical dimer.

26


Page 27 of 33

100

Relative Energy(kcal/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


80

60

40

20

0 -100

-50

0

50

100

150

200

Average Psi(°) Figure 4: The calculated relative energies of conformations at different psi angles using M062X/6-31G* level of theory.

27



0

-10

Interaction Energy(kcal/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 28 of 33

-20

-30

-40

-50

-60 -100

-50

0

50

100

150

200

Average Psi(°)

Figure 5: The calculated interaction energies between two monomers at different psi angles using M06-2X/6-31G* level of theory

28


Page 29 of 33

5

4


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3

1 2

1

3 0

2 -200

-150

-100

-50

0

50

100

150

200

Average Psi(°)

1

2

Figure 6: The conformational stability of monomer on surface MoS2.

29


3


20 0 -20

Interaction Energy(kcal/mol)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 30 of 33

-40 Van der Waals Interaction Energy Electrostatic Interaction Energy Total Interaction Energy

-60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -200

-150

-100

-50

0

50

100

150

200

Average Psi(°)

Figure 7: The interaction energy between MoS2 and monomer (amyloid peptide)

30


Page 31 of 33

6

Number of Hydrogen Bonds

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


5

4

3

2

1

0 -200

-150

-100

-50

0

50

100

150

200

Average Psi(°)

Figure 8: The calculated average number of hydrogen bonds in monomer (amyloid peptide).

31



5

4


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 32 of 33

3

2

1 3

1

0

2 -200

-150

-100

-50

0

50

100

150

200

Average Psi(°)

1

2

3

Figure 9: Interaction of dimers with surface of MoS2 and free energy for various conformations.

32


Page 33 of 33 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


TOC Graphic

On surface of MoS2 (Coil conformation)

Helical monomers of amyloid peptides

In aqueous solution (Beta sheet conformation)

33


Free Energy Landscape for Alpha-Helix to Beta-Sheet Interconversion

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