3. Quantum Mechanism (QM)
Electrons
Nuclei
Wave functions instead of Newton Eq.
High computation cost
Ab initio N4
N is # of base functions
Semi-empirical N3
Molecule of a couple of hundreds atoms
Pico-second(10-12
s) behavior
4. Molecular Mechanism (MM)
Atoms
Newton equations
Parameters from experiment and QM
force field
System with 100,000 atoms
µs (10-6
s) behavior
5. Force field
+−+−= ∑∑ 22
)()( eq
angle
eq
bonds
b krrkU θθθ
])[()]cos(1[
2 612
ij
ji
ij
ij
i ij ij
ij
dihedral n
n
r
qq
r
B
r
A
n
V
⋅
+−+−+ ∑∑∑ ∑ > ε
γφ
kb – bond parameter
kө --- angle parameter
Vn --- dihedral energy barrier
Van Der Waal radii
Partial charge set
6. Solvent effect
Oil in water
Hydrophobic interactions
Alcohol in water
Hydrophilic interactions
Explicit water
Solvent Accessible Surface
Surface Complementarity
8. Sidechains
The amino acids vary in their side chains (indicated in blue in the diagram).
The eight amino acids in the orange area are nonpolar and hydrophobic.
The other amino acids are polar and hydrophilic ("water loving").
The two amino acids in the magenta box are acidic ("carboxy" group in the side chain).
The three amino acids in the light blue box are basic ("amine" group in the side chain).
14. Why Is Docking Important?
Better understand the Machinery of Life
Enzyme-inhibitor class
Antibody-antigen class
Others
Engineered Protein Enzymes
Protein Therapies
Drug targets
15. Why Is Docking A Hard Problem?
Large Search Space !
Rigid Body Docking: 6D
Flexible Docking: 3N (N normal modes)
Structure Space: Continuous
16. Criteria for Good Docking
Orientations
Low Free Energy
Low Pseudo-Energy Based On force field
Large Surface Burial
Small van der Waals Overlaps
Good H-Bonding
Good Charge Complementarity
Polar/Polar Contacts Favoured
Polar/Non-Polar Contacts Disfavoured
17. Docking Search Strategies
Pseudo Random
Simulated Annealing / Monte Carlo
Genetic Algorithms
Directed Search
Geometric Hashing
Spherical Harmonic Surface Triangles
28. Lessons Learnt From CAPRI
Antibodies Often Bind Near Antigen's
Active Site
Expect Large Conformational Change
in Enzyme/Inhibitor Docking
Develop Better Models of Flexibility