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Computational Prediction of Binding Affinity
between Psychotropic Drugs and Neural
Cytoskeleton Elements
R. PIZZI1, T. RUT...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
• Tubulin is a globular
protein...
INTRO
• Microtubules are cylindrical polymers composed
by aligned tubulin dimers, alpha and beta-
tubulins, that polymeriz...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
• Microtubules (MTs) constitute...
Properties of microtubules
• In the last decades many studies have been carried out that
claim peculiar MTs quantum proper...
Properties of microtubules
• The present research follows other studies of our group that
with direct in-vitro experiments...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
INTRO
Project background
tubuli...
INTRO
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
- Our previous researches...
A deeper study of psychoactive drugs and their binding to
tubulin and MTs structures may help us to better understand
inte...
INTRO
Our aim
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Psychoactive drug...
To explore differences in binding with psychoactive drugs we
performed:
1. Molecular Dynamics (MD) to carry out conformati...
Material and Methods
I step: MD
Molecular Dynamics (MD):
• Configurations are generated by application of the Newton
equat...
MD:
We used the Ascalaph Designer software
This software combines Molecular Dynamics simulation in
liquid phase (with expl...
MD: Ascalaph Designer
• flexible tool with many possible parameterizations for the force
fields
• various dynamical optimi...
M D on ligands (psychoactive drugs):
1. The construction of the chemical structures was performed
using the Ascalaph Desig...
• Most biological functions are mediated by interactions
between proteins and ligands
• The bond with a ligand can induce ...
• Docking algorithm:
• The algorithm determines the geometric and electrostatic
complementarity between two molecular stru...
• HEX algorithm:
it uses an FFT evolution called SPF (Spherical Polar Fourier):
Each molecule is modelled in three dimensi...
HEX Clustering Docking Results
• It uses a clustering algorithm to group spatially similar
docking orientations:
• Each do...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Material and Methods
models
TUB...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Material and Methods
models
LIG...
• As control ligand we used taxol, a toxic substance that
increases microtubule polymerization by binding to the
filament ...
Results
Taxol in tubulin Taxol in MT
Taxol positions:
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Results
C.LSD ligand in MTs
A.C...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Results
Alpha helix
Beta sheet
...
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Results
Alpha helix
Beta sheet
...
Results
C.LSD ligand in Tubulin
B.Heroin ligand in Tubulin
A.Cocaine ligand in Tubulin
8th International Conference on APP...
Results
8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING.
Florence, 2014
Alpha helix
Beta sheet
...
Conclusions
• We conclude that cocaine and heroin have similar localization
in the tubulin structure, but not identical lo...
Conclusions
• As already amply demonstrated in our previous works, the
MT tubular structure shows to have an important fun...
Conclusions
• In the future we aim to widen the study with other similar
substances
• If their binding sites should reveal...
• A deeper study of consciousness-altering drugs and their
binding to tubulin and MTs may help us to understand the
comple...
References
• R. Pizzi , S. Fiorentini , G. Strini , M. Pregnolato, Exploring structural
and dynamical properties of Microt...
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Computational Prediction of Binding Affinity between Psychotropic Drugs and Neural Cytoskeleton Elements

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A study on the interaction betweem microtubules and consciousness-altering substances.

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Computational Prediction of Binding Affinity between Psychotropic Drugs and Neural Cytoskeleton Elements

  1. 1. Computational Prediction of Binding Affinity between Psychotropic Drugs and Neural Cytoskeleton Elements R. PIZZI1, T. RUTIGLIANO1, A. FERRAROTTI 2 and M. PREGNOLATO2 1Computer Science Department, University of Milan 2Department of Drug Sciences, University of Pavia
  2. 2. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 • Tubulin is a globular protein and the fundamental component of microtubules. • It is composed by two similar units, alpha and beta tubulin, bound very tightly together • . INTRO
  3. 3. INTRO • Microtubules are cylindrical polymers composed by aligned tubulin dimers, alpha and beta- tubulins, that polymerize in a helix that creates the microtubule.
  4. 4. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 • Microtubules (MTs) constitute the cytoskeleton of all the eukaryotic cells and are supposed to be involved in many key cellular functions. • MTs are claimed to possess peculiar functional properties that are under study. INTRO
  5. 5. Properties of microtubules • In the last decades many studies have been carried out that claim peculiar MTs quantum properties • Some hints and many theories seem to suggest that MTs may be involved in the consciuosness process. • Sir Roger Penrose, one of the major physicists of our age, maintains that inside MTs quantum superposition is sustained at room temperature, allowing a quantum computation that gives rise to consciousness. • Many scientists (e.g. Hameroff, Tuszinsky) support this or other similar theories.
  6. 6. Properties of microtubules • The present research follows other studies of our group that with direct in-vitro experiments and structural bioinformatics simulations have shown peculiar behavior of MTs • By means of specific physical measures of resonance and birefringence, that we also replicated in silico, we assessed a structural sensitivity of MTs in presence of electromagnetic field.
  7. 7. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 INTRO Project background tubulin, despite its symmetric structure, seems to have different internal forces that tend to resist a dynamic stabilization. However, in presence of electric field, although it tends to squash, it does not show any particular reaction. MTs react sharply to electromagnetic fields both in the experimental tests and in the simulations, showing to move and orient themselves along the field. The different behavior between microtubules and tubulin suggests that the tubular antenna-like shape of MTs is responsible of their peculiar properties
  8. 8. INTRO 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 - Our previous researches show that the peculiar properties of MTs could be due to their biological structure. - The present research aims to investigate with structural bioinformatics simulations the different behavior of tubulin and MTs in presence of consciousness-altering drugs - We meant to search for hints of a biological functional relationship between MTs and consciousness.
  9. 9. A deeper study of psychoactive drugs and their binding to tubulin and MTs structures may help us to better understand interactions and mechanisms. We examined: - A depressant drug (heroin) - A stimulant drug (cocaine) - A hallucinogen drug (LSD) INTRO Our aim 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Psychoactive drugs. Courtesy of Derek Snider.
  10. 10. INTRO Our aim 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Psychoactive drugs. Courtesy of Derek Snider.
  11. 11. To explore differences in binding with psychoactive drugs we performed: 1. Molecular Dynamics (MD) to carry out conformation optimization in water medium of cocaine, heroin, LSD 2. Docking procedures between structures (MTs and tubulin) and above mentioned drugs 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 INTRO Our aim
  12. 12. Material and Methods I step: MD Molecular Dynamics (MD): • Configurations are generated by application of the Newton equations of motion to all atoms simultaneously over a small time step to determine the new atomic positions and velocities • The force field is formed by the sum of molecular bonds and electrostatic forces • The total energy determines the evolution of this dynamical systems 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  13. 13. MD: We used the Ascalaph Designer software This software combines Molecular Dynamics simulation in liquid phase (with explicit water molecules) with a graphical interface Material and Methods I step: MD 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  14. 14. MD: Ascalaph Designer • flexible tool with many possible parameterizations for the force fields • various dynamical optimization techniques • graphical interface with many interactive methods for the development of molecular models • quantum computation • ab initio computational chemistry Material and Methods I step: MD 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  15. 15. M D on ligands (psychoactive drugs): 1. The construction of the chemical structures was performed using the Ascalaph Designer ab-initio Free Drawing 2. The next step was the optimization, i.e. the energy minimization, of all the built chemical structures (energy minimization algorithm: conjugate gradient method, stop conditions: gradient value = 0.001 and iteration number = 100) Material and Methods I step: MD 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  16. 16. • Most biological functions are mediated by interactions between proteins and ligands • The bond with a ligand can induce a conformational change that influences the activity or accessibility of other binding domains • We studied interactions between MTs, tubulin and drugs using HEX Protein Docking, a molecular docking software that allows both calculation and 3D visualization Source: http://hex.loria.fr/ Material and Methods II step: docking 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  17. 17. • Docking algorithm: • The algorithm determines the geometric and electrostatic complementarity between two molecular structures • It projects the molecule in a 3D grid, performing a distinction between surface and interior atoms. Then it evaluates the overlapping degree of the molecular penetration relative to all the possible orientations of the molecule ligand around the macromolecolar structure. Material and Methods II step: docking 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  18. 18. • HEX algorithm: it uses an FFT evolution called SPF (Spherical Polar Fourier): Each molecule is modelled in three dimensions using parametric functions that encode both the surface spatial potential distribution and their spherical polar coordinates Material and Methods II step: docking 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 The procedure searches for the best docking solution on the basis of a rigid 6-dimensional search on a rotational grid.
  19. 19. HEX Clustering Docking Results • It uses a clustering algorithm to group spatially similar docking orientations: • Each docking solution is first ordered by energy, and the lowest energy solution is considered the seed orientation for the first cluster. • Then the list of possible orientation is ordered on the basis of the intermolecular RMS distance between alpha-carbon chains • The process is repeated starting from the next lowest unassigned orientation, until all solutions have been assigned to a cluster. Material and methods Docking tool 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  20. 20. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Material and Methods models TUBULIN (PDB 1JFF) MICROTUBULES (NANO-D research group at INRIA Grenoble-Rhone-Alpes )
  21. 21. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Material and Methods models LIGANDS: cocaine LSD heroin
  22. 22. • As control ligand we used taxol, a toxic substance that increases microtubule polymerization by binding to the filament and stabilizing it. • Taxol lacks in psychotropic characteristics, and is typically associated with Tubulin in the databanks • Ligands (cocaine, LSD , heroin, taxol) were subjected to docking using HEX. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Results
  23. 23. Results Taxol in tubulin Taxol in MT Taxol positions:
  24. 24. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Results C.LSD ligand in MTs A.Cocaine ligand in MTs B.Heroin ligand in MTs Alpha helix Beta sheet MTs
  25. 25. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Results Alpha helix Beta sheet • MT the two ligands heroin e cocaine are close to a kind of niche (perhaps the access way). • cocaine, compared to heroin, seems to penetrate further into the structure •heroin assumes a more superficial position, moving in the direction of an alpha helix.
  26. 26. 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Results Alpha helix Beta sheet •heroin and cocain are positioned both at Chain A. •The third ligand, LSD, shows a completely different position with respect to the other two ligands •LSD assumes a superficial position in ​​ contact with the two Chains and an alpha​​ helix
  27. 27. Results C.LSD ligand in Tubulin B.Heroin ligand in Tubulin A.Cocaine ligand in Tubulin 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Alpha helix Beta sheet Tubulin
  28. 28. Results 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014 Alpha helix Beta sheet Results •cocaine and heroin show similar behavior: •they don’t appear to come in contact with any secondary structure, •they are present in a niche and positioned between chain A and B. •LSD takes a position similar to the other ligands, •LSD it is even more superficial and is only present at the level of one chain. Different observations have been made for tubulin:
  29. 29. Conclusions • We conclude that cocaine and heroin have similar localization in the tubulin structure, but not identical localization in MTs • LSD, however, assumes a completely different position compared to other ligands in both tubulin and in MT structures • The difference of the LSD behavior is evident in MT structure. • The control structure, Taxol, has a position completely different from the psychoactive substances, both in MT and in tubulin, suggesting that psychoactive substances have a different and specific role 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  30. 30. Conclusions • As already amply demonstrated in our previous works, the MT tubular structure shows to have an important functional role that cannot be found in the only tubulin structure. • Mainstream science is used to consider other structures as targets for psychotrope substances • In our study MTs show to bind the drugs more deeply than tubulin • It can be hypothesized that MT are not just storage proteins but play an active role in the binding of the psychotrope drugs
  31. 31. Conclusions • In the future we aim to widen the study with other similar substances • If their binding sites should reveal to be similar to those found for heroin, cocain, LSD, our hypothesis of an active role of MTs in the cosciousness process. • Studies on complete sets of MTs with many copies of ligands could be realized by adopting in the future powerful PC clusters or a Supercomputer facility.
  32. 32. • A deeper study of consciousness-altering drugs and their binding to tubulin and MTs may help us to understand the complex biological interface between conscious and unconscious state • The worldwide research on the functional role of MTs is indeed still open and evolving. Conclusions 8th International Conference on APPLIED MATHEMATICS, SIMULATION, MODELLING. Florence, 2014
  33. 33. References • R. Pizzi , S. Fiorentini , G. Strini , M. Pregnolato, Exploring structural and dynamical properties of Microtubules by means of artificial neural networks. In: Complexity Science, Living Systems and Reflexing Interfaces: New Models and Perspectives, IGI Global New York, 2012, pp. 78-91 • R. Pizzi , G. Strini , S. Fiorentini, V. Pappalardo and M. Pregnolato, Evidences of new biophysical properties of Microtubules, In: Focus on artificial neural networks, Nova Science, 2010, pp. 191-207. • R. Pizzi , S. Fiorentini (2009). Artificial Neural Networks Identify the Dynamic Organization of Microtubules and Tubulin Subjected to Electromagnetic Field. In: Recent Advances in Applied Computer Science. Genova, 17-19 Oct 2009, p. 103-106, ISBN: 978-960-474- 127-4

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