An integrated machine learning approach delineates an entropic expansion mechanism for the binding of a small molecule to α-synuclein
- Tata Institute of Fundamental Research, India
Figures
Figure 1 with 12 supplements
Deep neural network illustrating dimension reduction through β-Variational AutoEncoder.
(a) Conformational ensemble view of αS and αS-Fasudil ensemble, (b) A schematic of β-Variational Autoencoder (β-VAE), (c) Training and validation loss for β-VAE and (d) RMSE as a function of the β …
Figure 1—figure supplement 1
Distribution of the radius of gyration (Rg) of the αS and αS-Fasudil ensembles.
The Rg values of the initial structures used for the αS and αS-Fasudil simulation sare marked as symbols. The red diamond is the Rg of the starting structure of the αS-Fasudil simulation and the …
Figure 1—figure supplement 2
Distribution of end-to-end distance for the αS and αS-Fasudil ensembles.
The mean values of the distributions are marked.
Figure 1—figure supplement 3
Distribution of SASA for αS and αS-Fasudil ensembles.
The mean values of the distributions are marked.
Figure 1—figure supplement 4
Residue wise percentage secondary structure of helical nature in the αS and αS-Fasudil ensembles.
Figure 1—figure supplement 5
Residue wise percentage secondary structure of sheet nature in the αS and αS-Fasudil ensembles.
Figure 1—figure supplement 6
Residue wise percentage secondary structure of coil nature in the αS and αS-Fasudil ensembles.
Figure 1—figure supplement 7
Each blue diamond label represents the RMSD (nm) w.r.t the starting structure of aSyn-fasudil simulation.
The value associated with each diamond label corresponds to the timescale of simulation.
Figure 1—figure supplement 8
Fraction of helix content in the starting structures of the αS-Fasudil and αS simulations.
Figure 1—figure supplement 9
Fraction of β-sheet content in the starting structures of the αS-Fasudil and αS simulations.
Figure 1—figure supplement 10
Fraction of coil content in the starting structures of the αS-Fasudil and αS simulations.
Figure 1—figure supplement 11
Total SASA of the starting structures of the αS-Fasudil and αS simulations.
Figure 1—figure supplement 12
Residue wise SASA of the starting structure of the αS-Fasudil (red square) and αS (blue squares) simulations.
Figure 2
Free energy landscape using the latent space of β-VAE indicates greater conformational space sampled by αS in presence of fasudil.
The free energy landscape of (a) αS and (b) αS-Fasudil system as determined from the latent dimensions of β-VAE.
Figure 3 with 11 supplements
Markov state model captures three and six states of αS and αS-Fasudil system, respectively.
(a) A flowchart of the process of building a Markov State Model (MSM).(b, c) Implied timescales plot of the αS and αS-Fasudil systems. (c) Macrostate populations of the 3-state and 6-state MSM of …
Figure 3—figure supplement 1
Comparison of VAMP-2 score from VAE and tICA of pairwise distances, reduced to two dimensions for the αS-Fasudil simulation.
Figure 3—figure supplement 2
Comparison of VAMP-2 score from VAE and tICA of pairwise distances, reduced to two dimensions for the αS simulation.
Figure 3—figure supplement 3
The Chapman-Kolmogorov test performed for the six state Markov State Model of the αS-Fasudil ensemble.
Figure 3—figure supplement 4
The implied timescale (ITS) plot αS-Fasudil simulation for the block of 10 μs to 70 μs.
Figure 3—figure supplement 5
Distribution of Rg of the αS ensemble and the 60 μs slice (10 μs-70 μs) of the αS-Fasudil simulation trajectory.
Figure 3—figure supplement 6
Distribution of Rg of the αS ensemble and the 60 μs slice (966 μs to 1026 μs) of the αS-Fasudil simulation trajectory.
Figure 3—figure supplement 7
The implied timescale (ITS) plot αS-Fasudil simulation for the block of 966 μs to 1026 μs.
Here too we see 6 states.
Figure 3—figure supplement 8
VAMP-2 score as a function of the number of microstates in for the αS-Fasudi ensembles for a latent space of four dimensions.
Figure 3—figure supplement 9
ITS plot of the αS-Fasudi simulation using the four dimension of the VAE.
Here too we see 6 states.
Figure 3—figure supplement 10
VAMP-2 score as a function of the number of microstates in for the αS-Fasudil ensemble.
Figure 3—figure supplement 11
VAMP-2 score as a function of the number of microstates in for the αS ensemble.
Figure 4 with 1 supplement
Intrapeptide residue-wise contact map of the macrostates of αS-Fasudil system indicates that the six states represent distinct ensembles.
Intrapeptide residue-wise contact probability maps of (a) six macrostates (FS1 to FS6) in the presence of fasudil. A contact is considered if the Cα atoms of two residues are within a distance of 8Å …
Figure 4—figure supplement 1
Residue-wise percentage secondary structure estimated for each of the six macrostates of αS monomer simulated in the presence of fasudil.
Figure 5 with 1 supplement
Intrapeptide residue-wise contact map of the macrostates of αS system indicates that the three states represent distinct ensembles.
Intrapeptide residue-wise contact probability maps of the three macrostates (MS1 to MS3) in neat water. A contact is considered if the Cα atoms of two residues are within a distance of 8Å of …
Figure 5—figure supplement 1
Residue-wise percentage secondary structure estimated for each of the three macrostates of αS monomer simulated in neat water.
Figure 6 with 4 supplements
Projection of contact maps of αS and αS-Fasudil macrostates using denoising convolutional VAE.
(a) Schematic of denoising convolutional variational autoencoder (b) Latent space of the contact map of αS and αS-Fasudil metastable states. (c) SSIM and PSNR values for αS and αS-Fasudil metastable …
Figure 6—figure supplement 1
Loss profile of (a) CVAE indicating overfitting (b) DCVAE indicating no overfitting.
Figure 6—figure supplement 2
Denoised output of the contact map of the αS macrostates.
Figure 6—figure supplement 3
Denoised output of the contact map of the αS-Fasudil macrostates FS1, FS2, and FS3.
Figure 6—figure supplement 4
Denoised output of the contact map of the αS-Fasudil macrostates FS4, FS5, and FS6.
Figure 7
Contact map between fasudil and αS, indicates that fasudil interacts with distinct regions of αS in the six macrostates.
(a) Contact probability map of residue-wise interaction of fasudil with αS.(b) Overlay of representative conformations from the six macrostates (FS1 to FS6) along with the bound fasudil molecules. …
Figure 8 with 3 supplements
Entropy of αS system is modulated to a greater extent in presence of fasudil, with insignificant contribution from the solvent entropy.
(a) Total Protein entropy of the metastable states of αS and αS-Fasudil calculated from the torsion angles, relative to a fully flexible chain (b) Total water entropy in αS and αS-Fasudil system and …
Figure 8—figure supplement 1
Translational and Rotational entropy of water.
(a) Translational entropy of water and (b) Rotational entropy of water in αS and αS-Fasudil system.
Figure 8—figure supplement 2
Residue-wise entropy of αS states populated in water and in the presence of fasudil.
Figure 8—figure supplement 3
Residue-wise sidechain entropy of αS states populated in water and in the presence of fasudil.
Figure 9
Mean first passage time for αS and αS-Fasudil ensembles indicates that a decrease in the transition time to the most entropic state in presence of fasudil, thereby potentially trapping S in the intermediate states.
The rate network obtained from MFPT analysis for the (a) 3-state MSM of the αS ensemble in neat water and (b) 6-state MSM of the αS-Fasudil ensemble. The sizes of the discs is proportional to the …
Author response image 1
Left figure : Distribution of the radius of gyration (Rg) of the 23 apo simulation (as shown in the colourbar) and holo simulation (black).
Right figure : Mean and standard deviation (as error bar) of the Rg of the 23 apo (colourbar) and holo simulations (black).
Author response image 2
The Chapman-Kolmogorov test performed for the three state Markov State Model of the αS ensemble.
Author response image 3
Autocorrelation of the first principal component of the backbone dihedral for the apo (colourbar) and holo (black) simulation.
Author response image 4
Autocorrelation of the second principal component of the backbone dihedral for the apo (colourbar) and holo (black) simulation.
Author response image 5
Author response image 6
Distribution of (a)Rg, (b) Ree, (c) SASA and of the apo ensemble and a 60 μs slice of the holo simulation trajectory.
(d) ITS plot of the 60 μs chunk.
Author response image 7
Distribution of radius of gyration for the three and six macrostates in the apo and holo simulation respectively.
Tables
Table 1
The size of the simulation box for the 23 αS simulations.
| Conformation number | Cubic Box size (nm) |
|---|---|
| 1 | 12.14 |
| 2 | 11.33 |
| 3 | 13.55 |
| 4 | 10.41 |
| 5 | 10.97 |
| 6 | 10.44 |
| 7 | 10.10 |
| 8 | 11.44 |
| 9 | 10.57 |
| 10 | 10.75 |
| 11 | 11.34 |
| 12 | 10.35 |
| 13 | 13.38 |
| 14 | 10.08 |
| 15 | 10.38 |
| 16 | 11.78 |
| 17 | 11.92 |
| 18 | 9.37 |
| 19 | 10.15 |
| 20 | 11.16 |
| 21 | 11.24 |
| 22 | 11.46 |
| 23 | 12.00 |
