protein structural organization

CZ5225 Methods in Computational BiologyCZ5225 Methods in Computational Biology

Lecture 7: Protein Structure and Lecture 7: Protein Structure and Structural ModelingStructural Modeling

Prof. Chen Yu ZongProf. Chen Yu Zong

Tel: 6874-6877Tel: 6874-6877Email: Email: [email protected]@nus.edu.sghttp://xin.cz3.nus.edu.sghttp://xin.cz3.nus.edu.sg

Room 07-24, level 7, SOC1, NUSRoom 07-24, level 7, SOC1, NUSAugust 2004August 2004

mailto:[email protected]

http://xin.cz3.nus.edu.sg/

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Protein Structural OrganizationProtein Structural Organization

Proteins are made from just 20 kinds of amino acids

33

Protein Protein Structural Structural OrganizationOrganization

Protein has four levels of structuralorganization

44

Protein Structure Determines Its Interaction with Protein Structure Determines Its Interaction with Other Molecules:Other Molecules:

Protein-Protein InteractionProtein-Protein Interaction

55


Protein-DNA InteractionProtein-DNA Interaction

66


Protein-RNA InteractionProtein-RNA Interaction

77


Protein-Drug InteractionProtein-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

88

Protein Structure and Motions:Protein Structure and Motions:

Protein-Drug InteractionProtein-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

99

Protein structure and motions:Protein structure and motions:

Movie Show:

Drug Binding Induced Conformation Change in Protein

1010

Protein structure and motions:Protein structure and motions:

Movie Show:

Protein transient opening for ligand or drug binding and dissociation:

1111

Protein structure: Lowest Free Energy StateProtein structure: Lowest Free Energy State

Modeling of Protein Structure in DifferentEnvironment:

Finding the global minimum free energy state

Question:

1. No. of possible conformations of a protein.

2. Computing cost for searching these conformations

1212

Structural Modeling: Structural Modeling: Basic Interactions and Their ModelsBasic 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.

1313


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.

1414


The bending energy equation is also based on Hooke's law

1515


The bending energy equation is also based on Hooke's law

1616


The torsion energy is modeled by a simple periodic function

Why?

1717


Torsion energy as a function of bond rotation angle.

1818


The non-bonded energy accounts for repulsion, van der Waals attraction, and electrostatic interactions.

1919


• 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.

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Hydrogen Bond:

N-H … ON-H … NO-H … NO-H … O

Modeled by VdW+electrostatic

Modeled by More potential


Complete Hamiltonian:

bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

2222


Concept of energyscale is Important for molecular Modeling

2323


Concept of energy scale is Important for molecular modeling

2424


Sources of force parameters:

Bonds, VdW, Electrostatic (for amino acids, nucleotides only):• AMBER: J. Am. Chem. Soc. 117, 5179-5197• CHARMM: J. Comp. Chem. 4, 187-217

H-bonds (Morse potential):• Nucleic Acids Res. 20, 415-419.• Biophys. J. 66, 820-826

Electrostatic parameters of organic molecules need to be computed individually by using special software (such as Gaussian)

bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

2525

Energy Landscape Energy Landscape for DNA Base Flipping Movementfor DNA Base Flipping Movement

Phys. Rev. E62, 1133-1137 (2000).

2626


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 forXi=x(r,theta,phi) etc.

bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

2727


bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

Structural Modeling Method I:

Conformation search:

Phi -> Phi+dphixi -> xi+dxi; yi -> yi+dyi; zi -> zi+dziE -> E +dE

All possible states can be exploredConformation spaceEnergy landscape

Q: Can you write a simple conformation search program?

2828


bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

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/dzidxi=C*Fxinew xi=xi+dxi

Energy minimization can only go down hill. Why?

2929


bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

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

3030


bondednon ijij

ji

ij

ij

ij

ijrra

bondH

bondS

rra

rotationbond

n

eqbendinganglebond

eqrstretchbondatoms

r

qq

r

B

r

AVeV

VeVn

v

krrkm

pH

][])1([

])1([)]cos(1[

2

)(2

1)(

2

1

2

61202)(

0

02)(

0

222

'0

'0

Structural Modeling Method III:Molecular Dynamics Simulation:

3131

Molecular Dynamics SimulationMolecular Dynamics SimulationChallenge: 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: Technique Speed-up factor

Reduction of degrees of freedom up to 100

Parallelization 10~100Multiple time-step integration 10~

Deformation of interaction potential orincrease space dimension

10~

Scaling of system parameters (T, mass, etc) 3~Efficient search of nearest neighbors 3

Miscellaneous tricks (Newton's 3rd law etc) 2

Curr. Opin. Struc. Biol. 7, 181 (1997)

3232

CZ5225 Methods in Computational Biology Assignment 2Assignment 2

protein structural organization

Documents

protein protein structure

structure of disease

useful protein structure

basic interactions

protein transient opening

hookes law structural

electrostatic interactions

electrostatic energy