Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 ›...
Transcript of Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 ›...
![Page 1: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/1.jpg)
Computational Drug Design & Molecular Dynamics :Computational Drug Design & Molecular Dynamics :Computational Drug Design & Molecular Dynamics :Computational Drug Design & Molecular Dynamics :
an HPC perspectivean HPC perspectivean HPC perspectivean HPC perspective
Jean-Philip Piquemal
Sorbonne Université
& Institut Universitaire de France
& University of Texas at Austin
Le Lab Quantique
02/04/2020
![Page 2: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/2.jpg)
Drug Design & High-Performance Computing
![Page 3: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/3.jpg)
Source top 500 https://commons.wikimedia.org/w/index.php?curid=8740585
![Page 4: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/4.jpg)
The huge increase of HPC capabilities now enable to use advanced
computational chemistry approaches.
The situation changed…
![Page 5: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/5.jpg)
Computational Chemistry
Linus Pauling (1954):
The nature of the chemical bond
Walter Kohn & John Pople (1998):
� development of computational quantum chemistry
� Density Functional Theory (DFT)
Martin Karplus, Michael Levitt et Arieh Warshel (2013):
� Molecular Dynamics
� Chemical reactivity Modeling
![Page 6: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/6.jpg)
Atomistic simulations:
Quantum or Classical Mechanics?
Quantum Mechanics: Quantum Chemistry
Classical mechanics: Molecular dynamics
![Page 7: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/7.jpg)
Molecular Dynamics:
Integration timestep - 1 femtoseconde
Accessible timescale about a few milliseconds
(DE. Shaw research).
Bond vibration - 1 fs
Collective vibrations- 1 ps
Conformational transition- ps or more
Enzymatic catalysis- microsecond/millisecond
Docking (ligand biding to a target) - micro/millisecond
Protein folding - millisecond/second
Timescales…and Biology
![Page 8: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/8.jpg)
Timescales (2)…
Molecular Dynamics:
Integration timestep - 1 femtoseconde
Accessible timescale about a few milliseconds
(DE. Shaw research).
![Page 9: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/9.jpg)
9
MOLECULAR SIMULATION AT A GLANCE
Molecular Dynamics notablyallows one to :
atomic-scalecomputer-aided
design and engineering
virtualmicroscope
study complex molecularprocesses with atomic-scale
space-time resolution
predict the propertiesof new molecules,
materials, and nanodevices
![Page 10: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/10.jpg)
10
INTRODUCTION TO NEW GENERATION MOLECULAR
DYNAMICS
TO BE QUANTITATIVE/PREDICTIVE, SUCH SIMULATIONS MUST RELY ON MORE PHYSICS
POLARIZABLE FORCE
FIELDS
(N-BODY PHYSICS)
CLASSICAL FORCE
FIELDS
(2-BODY PHYSICS)
![Page 11: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/11.jpg)
Molecular dynamics
![Page 12: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/12.jpg)
1st simulations (1957/59)
Hard spheresdures
(computations of the collision time)
≤∞
>=
dr
drruij
0)(
Solide pahse Liquide phase Interface liquid-vapor
N=32: 7000 collisions / h
N=500: 500 collisions / h
IBM-704:
Production time
~20000 step
N=32 →→→→ 6.5x105 coll. →→→→ 4 days
N=500 →→→→ 107 coll. →→→→ 2.3 years
![Page 13: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/13.jpg)
First properties (1964)
CDC-3600
RDF
MSD
VACF
864 particules
Time per step ~ 45s
Production time ~20000 steps ≅≅≅≅ 10 days!
(today a few secondes on a cellphone ;)…)
![Page 14: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/14.jpg)
Docking & drug design: MD for drug discovery
Target: protein
(or enzyme)
Ligand (drug)+
Protein-ligand complex
![Page 15: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/15.jpg)
Docking & drug design: MD for drug discovery
![Page 16: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/16.jpg)
16
Computing the most favourable location for a drug interacting with a
protein is “as hard” as landing a probe on a comet (i.e. ESA Rosetta
mission).
Great need of computational precision !
Docking & drug design: MD for drug discovery
![Page 17: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/17.jpg)
![Page 18: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/18.jpg)
Target Selection
Hit finding (Virtual screening, databases…)
Hit to lead (progressive elimination)
docking, sélectivity
Lead Optimization (best hit optimization)
Drug Development
Research
Discovery of a new drug: a long process…
![Page 19: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/19.jpg)
Rational design and molecular modelling in drug discovery.
![Page 20: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/20.jpg)
Rational design in the industry
![Page 21: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/21.jpg)
Rational design: the need for physics,
mathematics and computer sciences
Crédits: Extreme tech
![Page 22: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/22.jpg)
To perform new generation MD simulations:
you need advanced softwares able to use
modern hardware
3 steps :1. thermalization2. Equilibration 3. Production
CPUs (massive parallelism)GPUs (massive parallelism)OPUs/TPUsQuantum Computing
Dedicated Hardware (DE. Shaw) /FGPAs
![Page 23: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/23.jpg)
23
Tinker-HP high performance and high precision
Tinker-HP
Tinker-HP is a new molecular modeling platform allowing for moleculardynamics simulations using highly precise new methods
(new generation polarizable force fields).
Massively parallel MPI implementation on CPUs and GPUs.
Objectives : to simulate the dynamical time evolution of a molecular systemthanks to Newton laws.
Such methodology is million times faster than quantum mechanics butremains accurate thanks to new generation force fields grounded onquantum chemistry and including many-body effects.
![Page 24: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/24.jpg)
24
Grand challenge: optimization and applications of Tinker-HP
Tinker-HP
Tinker-HPL. Lagardère, L.-H. Jolly, F. Lipparini, F. Aviat, B. Stamm, Z. F. Jing, M. Harger, H. Torabifard, G. A. Cisneros,
M.J. Schnieders, N. Gresh, Y. Maday, P. Ren, J.. W. Ponder, J.-P. Piquemal,
Chemical Science, 2018, 9, 956-972 (open access), DOI: 10.1039/C7SC04531J
Website: http://tinker-hp.ip2ct.upmc.fr/
![Page 25: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/25.jpg)
3.5 millions atoms possible with petascale machines. Full virus using pre-exascale (EMC2 ERC project)
Mixed-precision: multi-GPUs/GPUs-CPUs.
Perspectives: HIV-1 nucleocapsid & Capsid
![Page 26: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/26.jpg)
But a coranovirus decided to change our plans…
![Page 27: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/27.jpg)
27
20252022
Protein
10,000atoms
3,500,000 atoms
100,000,000 Atoms
ribosome cytoplasm
TINKER-HP 2.0
2006 2018
TINKER
TINKER-HP 1.0
PETASCALE (PRE)EXASCALE
10,000,000,000 atoms
Cell
EXASCALE
Towards a cell (or virus)…ERC Synergy EMC2(grant agreement No 810367)Extreme-scale Mathematically-based Computational Chemistry
![Page 28: Computational Drug Design & Molecular Dynamics : an HPC ... › ... › 2020 › 04 › Piquemal_LeLabQuan… · Tinker-HP is a new molecular modeling platform allowing for molecular](https://reader036.fdocuments.us/reader036/viewer/2022081612/5f0f8b2d7e708231d444afb8/html5/thumbnails/28.jpg)
28