1. CZ5225 Methods in Computational Biology Lecture 7: Protein Structure and Structural Modeling Prof. Chen Yu Zong Tel: Room 07-24, level 7, SOC1, NUS August 2004

2. Protein Structural Organization
Proteins are made from just 20 kinds of amino acids

3. Protein Structural Organization
Protein has four
levels of structural
organization

4. Protein Structure Determines Its Interaction with Other Molecules: Protein-Protein Interaction

5. Protein Structure Determines Its Interaction with Other Molecules: Protein-DNA Interaction

6. Protein Structure Determines Its Interaction with Other Molecules: Protein-RNA Interaction

7. Protein Structure Determines Its Interaction with Other Molecules: Protein-Drug Interaction
Mechanism of
Drug Action:
A drug interferes with the function of a disease protein by binding to it.
This interference stops the disease process
Drug Design:
Structure of disease protein is very useful

8. Protein Structure and Motions: Protein-Drug Interaction
Mechanism of
Drug Action:
A drug interferes with the function of a disease protein by binding to it.
This interference stops the disease process
Drug Design:
Structure of disease protein is very useful

9. Protein structure and motions:
Movie Show:
Drug Binding Induced Conformation Change in Protein

10. Protein structure and motions:
Movie Show:
Protein transient opening for ligand or drug binding and dissociation:

11. Protein structure: Lowest Free Energy State
Modeling of Protein
Structure in Different
Environment:
Finding the global
minimum free energy
state
Question:
No. of possible conformations of a protein.
Computing cost for searching these conformations

12. Structural Modeling: Basic Interactions and Their Models
The stretching energy equation is based on Hooke's law. The "kb" parameter controls the stiffness of the bond spring, while "ro" defines its equilibrium length.

13. Structural Modeling: Basic Interactions and Their Models
The stretching energy equation is based on Hooke's law. The "kb" parameter controls the stiffness of the bond spring, while "ro" defines its equilibrium length.

14. Structural Modeling: Basic Interactions and Their Models
The bending energy equation is also based on Hooke's law

15. Structural Modeling: Basic Interactions and Their Models
The bending energy equation is also based on Hooke's law

16. Structural Modeling: Basic Interactions and Their Models
The torsion energy is modeled by a simple periodic function
Why?

17. Structural Modeling: Basic Interactions and Their Models
Torsion energy as a function of bond rotation angle.

18. Structural Modeling: Basic Interactions and Their Models
The non-bonded energy accounts for repulsion, van der Waals attraction, and electrostatic interactions.

19. Structural Modeling: Basic Interactions and Their Models
van der Waals attraction occurs at short range, and rapidly dies off as the interacting atoms move apart.
Repulsion occurs when the distance between interacting atoms becomes even slightly less than the sum of their contact distance.
Electrostatic energy dies out slowly and it can affect atoms quite far apart.

20. Structural Modeling: Basic Interactions and Their Models
Hydrogen Bond:
N-H … O
N-H … N
O-H … N
O-H … O
Modeled by
VdW+electrostatic
Modeled by More potential

21. Structural Modeling: Basic Interactions and Their Models
Complete Hamiltonian:

22. Structural Modeling: Basic Interactions and Their Models
Concept of energy
scale is Important
for molecular
Modeling

23. Structural Modeling: Basic Interactions and Their Models
Concept of energy scale is Important for molecular modeling

24. Structural Modeling: Basic Interactions and Their Models
Sources of force parameters:
Bonds, VdW, Electrostatic (for amino acids, nucleotides only):
AMBER: J. Am. Chem. Soc. 117,
CHARMM: J. Comp. Chem. 4,
H-bonds (Morse potential):
Nucleic Acids Res. 20,
Biophys. J. 66,
Electrostatic parameters of organic molecules need to be computed individually by using special software (such as Gaussian)

25. Energy Landscape for DNA Base Flipping Movement
Phys. Rev. E62, (2000).

26. Structural Modeling: Basic Interactions and Their Models
From structure (x,y,z coordinates) to energy function:
rij=sqrt((xi-xj)**2+(yi-yj)**2+(zi-zj)**2)
cos(theta_i)=(xj-xi)*(xk-xi)+(yj-yi)*(yk-yi)+(zj-zi)*(zk-zi))/(rij*rik)=
Aij*Aik+Bij*Bik+Cij*Cik
cos(phi)=[(Aik*Bkl-Bik*Akl)*(Aik*Bij-Bik*Aij)+
(Akl*Cik-Ckl*Aik)*(Aij*Cik-Cij*Aik)+
(Bik*Ckl-Cik*Bkl)*(Bik*Cij-Cik*Bij)]/(Pi*Pk)
Pi=sin(theta_i)
Pk=sin(theta_k)
Homework: derive or find formula for
Xi=x(r,theta,phi) etc.

27. Structural Modeling: Basic Interactions and Their Models
Structural Modeling Method I:
Conformation search:
Phi -> Phi+dphi
xi -> xi+dxi; yi -> yi+dyi; zi -> zi+dzi
E -> E +dE
All possible states can be explored
Conformation space
Energy landscape
Q: Can you write a simple
conformation search program?

28. Structural Modeling: Basic Interactions and Their Models
Structural Modeling Method II:
Energy minimization:
General methods in Numerical Recipes
Force guided approach:
Initialize: xi -> xi+dxi
Compute potential energy change:
V -> V +dV
Determine next movement:
Fxi=-dV/dxi; Fyi=-dV/dyi; Fzi=-dV/dzi
dxi=C*Fxi
new xi=xi+dxi
Energy minimization can only go down hill. Why?

29. Structural Modeling: Basic Interactions and Their Models
Structural Modeling Method III:
Molecular Dynamics Simulation:
Time-dependent motion trajectory based on laws of classical physics.
Advantage: "Accurate" dynamics.
Disadvantage: Short-time event only.
Application: "All purpose", most widely used approach.
Curr. Opin. Struct. Biol. 6, 232 (1996).
Detailed description of MD general theory

30. Structural Modeling: Basic Interactions and Their Models
Structural Modeling Method III:
Molecular Dynamics Simulation:

31. Molecular Dynamics Simulation
Challenge: Time-scale gap
Bio-events: 10-3~10s
MD: 10-6s on 200-node parallel computer for 30aa peptide
Gap: Need to increase computing speed by >>1000
Time-saving techniques in development:

32. CZ5225 Methods in Computational Biology Assignment 2