the physics of computational drug discovery
DESCRIPTION
This is a short lecture that I gave to school childrenin June 2012, at University College Dublin, Ireland about the amazing "Physics of Drug Discovery." It can be an interesting template to introduce students in the field of statistical physics.TRANSCRIPT
- The Physics of Drug Discovery -
Shourjya Sanyal
Table of Content
Topic No Of Slides
Introduction To Drug Designing
5
Molecular Dynamics (MD) Simulation
5
Free Energy Calculations
5
Hands on Training :
MD Simulation Setup and Run
10
Rational Drug Designing
Rational Drug Designing
Rational Drug Designing
Rational Drug Designing
Rational Drug Designing
Absorption Distribution Metabolism Elimination
MD Simulations
Dynamics: calculating trajectories
• Trajectory: positions as function of time: r i (t) • How does one determine r i (t) from Fi = mi . ai ?
Fi = mi . Ai = mi . dvi /dti = mi . d2 ri /dti 2
• Simple case where acceleration is constant a = dv/dt v = at + v
o
MD Simulations
Treatment of solvent
• Implicit: The macromolecule interacts only with itself, but the electrostatic interactions are modified to account for the solvent• Explicit representation The macromolecule is surrounded by solvent molecules (water, ions) with which the macromolecule interacts. Specific nonbond interactions are calculated
MD Simulations
Periodic boundary conditions
For explicit representation of solvent the boundaries of the system must be represented for periodic system.
Permits the modeling of very large systems, but introduces a level of periodicity not present in nature.
MD Simulations
MD Simulations
Molecular dynamics:Integration timestep - 1 fs, set by fastest varying force.
Accessible timescale: about 10 nanoseconds.
Timescale Limitations
Free Energy Calculations
Energy of binding ∆H must become more negative The energetic interactions between ligand and receptor have to become more favorable
Free Energy Calculations
The energy terms can be calculated according to force fields
Free Energy Calculations
Dispersive interactions: London forces and van der Waals
Free Energy Calculations
Free Energy Calculations
Energy Surface Exploration by Simulation..
MD Simulation Setup
Methods for Determining Atomic Structures
NMR (nuclear magnetic resonance) : Absorption of electromagnetic waves
MD Simulation Setup
Obtaining X-Ray structures
The arrangement of atoms in the crystal gives rise to a diffraction pattern.
MD Simulation Setup
MD Simulation Setup
MD Simulation Setup
Step One: Prepare the Protein Topology
> For this tutorial, we will utilize T4 lysozyme L99A/M102Q (PDB code 3HTB). Go to the RCSB website and download the PDB text for the crystal structure.
> Seperate out Ligand and Parent Molecule.
grep JZ4 3HTB_clean.pdb > JZ4.pdb
> Create Topology File for Molecule.
pdb2gmx -f 3HTB_clean.pdb -o 3HTB_processed.gro -water spc
MD Simulation Setup
Step Two : Prepare the Ligand Topology
For this tutorial, we will use PRODRG to generate a starting topology for our ligand, JZ4. Go to the PRODRG site and upload your JZ4.pdb file. The server presents you with several options for how to treat your ligand.
> Include topology of ligand
; Include ligand topology#include "JZ4.itp"
MD Simulation Setup
Step Three : Solvate The System In Box
Define the box
editconf -f 3HTB_JZ4.gro -o 3HTB_JZ4_box.gro -bt cubic -d 1.0
Adding water ions to the box
genbox -cp 3HTB_JZ4_box.gro -cs spc216.gro -p 3HTB_JZ4.top -o 3HTB_JZ4_boxwater.gro
MD Simulation Setup
Step Four : Energy Minimization
Now that the system is assembled, create the binary input using grompp using this input parameter file:
grompp -f enermin.mdp -c 3HTB_JZ4_boxwater.gro -p 3HTB_JZ4.top -o em.tpr
We are now ready to invoke mdrun to carry out the EM:
mdrun -v -deffnm em
MD Simulation Setup
Step Five : Analysis
Energy Landscape
g_energy -f em.edr -o tot.xvg
Structural Analysis
g_rama -f em.trr -s em.tpr -o myrama.xvg
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