Interactions between biomolecules are stereospecific

Research of Inhibitor-enzyme interaction using Autodock

• (google docking movie autodock or go autodock page directly)

Final Docked Energy

Energy evaluation in Autodock

ΔGsolvation

Grid Maps

Search for optimal conformations of ligands

• Translation, Torsion, Orientation

• 103x3611x363

Computational procedure of GA

1. Start from, say, 100 random conformations.

2. Calculate energies of ligand-protein complexes for 100 structures.

3. To generate new conformations, the ligand conformations of lower energy are weighted more to generate new conformations.

4. Repeat 2-3 until the calculation converges.

(look at ‘movie’ at the autodock website!)

Subroutine of random number generation

• REAL FUNCTION RANF ( DUMMY )

• C *******************************************************************• C ** RETURNS A UNIFORM RANDOM VARIATE IN THE RANGE 0 TO 1. **• C ** **• C ** *************** **• C ** ** WARNING ** **• C ** *************** **• C ** **• C ** GOOD RANDOM NUMBER GENERATORS ARE MACHINE SPECIFIC. **• C ** PLEASE USE THE ONE RECOMMENDED FOR YOUR MACHINE. **• C *******************************************************************

• INTEGER L, C, M• PARAMETER ( L = 1029, C = 221591, M = 1048576 )

• INTEGER SEED• REAL DUMMY• SAVE SEED• DATA SEED / 0 /

• C *******************************************************************

• SEED = MOD ( SEED * L + C, M )• RANF = REAL ( SEED ) / M

• RETURN• END

Lamarckian Genetic Algorithm (LGA)

BIM3-PDK1

Testing Docking Methods

• Automated Docking Using a Lamarckian GeneticAlgorithm and an Empirical Binding Free Energy Function

• GARRETT M. MORRIS, DAVID S. GOODSELL,ROBERT S. HALLIDAY, RUTH HUEY, WILLIAM E. HART,RICHARD K. BELEW, ARTHUR J. OLSON

• Journal of Computational Chemistry,Vol. 19, No. 14, 1693-1662 (1998)

• GOLD- Genetic Optimisation for Ligand Docking

• Scoring Function- Goldscore ：

Fitness ＝ S(hb_ext) ＋ 1.375×S(vdw_ext) ＋ S(hb_int) ＋ S(int) ＋

S(bar)

• van der Waals‘ forces → Lennard-Jones potential

• Hydrogen bond →

Introduction- GOLD software

Introduction- Genetic Algorithm

Encoding

Initial population Generation

START

Crossover Mutation

Evaluation Decoding

Solutions

FitnessComputation

Selection

Termination ?

STOP

NewPopulation

N

Y

Biased toward better

‘fitters’!

GA - coding

GA- introduction to operations

Introduction- GOLD

Default 1 2 timesspeed-up

3 timesspeed-up

7-8 timesspeed-up

Population Size 100 100 100 100

Selection Pressure 1.1 1.1 1.1 1.1

No. of Operations 100000 50000 30000 10000

No. of Islands 5 5 3 1

Niche Size 2 2 2 2

Migrate 10 10 10 0

Mutate 95 95 95 100

Crossover 95 95 95 100

Sset as 0 if # of island is

1 because

no migratio

n between ‘islands’.operations

A random pick: keep the frequency this ratio!

100 populations

each!

Selection Pressure

• Each of the genetic operations (crossover, migration, mutation) (see Operator Weights: Migrate, Mutate, Crossover) takes information from parent chromosomes and assembles this information in child chromosomes. The child chromosomes then replace the worst members of the population.

• • • The selection of parent chromosomes is biased towards those of high fitness, i.e. a fit chromosome is more likely

to be a parent than an unfit one. • • • The selection pressure is defined as the ratio between the probability that the most fit member of the population is

selected as a parent to the probability that an average member is selected as a parent. Too high a selection pressure will result in the population converging too early.

• • • For the GOLD docking algorithm, a selection pressure of 1.1 seems appropriate, although 1.125 may be better for

library screening where the aim is faster convergence.• • • Changes to genetic algorithm parameters should be made with care

(see Controlling Accuracy and Speed with Genetic Algorithm Parameter Settings)

Note• Why some fitness function is higher than final score during docking ?• Information on the Progress of Docking Runs• … •  • During a docking run, the fitness score may appear to get worse as the • docking proceeds. This is due to the fact that the effects of poor H-

bond • geometry and close nonbonded contacts are artificially down-weighted

at • early stages of the docking (annealing). Only the final fitness score (i.e. • from the completed docking) has any meaning. • … •  • Van der Waals and Hydrogen Bonding Annealing Parameters• When GoldScore is being used, the annealing parameters, Van der • Waals and Hydrogen Bonding, allow poor hydrogen bonds to occur at

the • beginning of a genetic algorithm run, in the expectation that they will • evolve to better solutions.• (this is in more details now! Can read later!)•  •  The selection pressure is defined as the ratio between the probability

that • the most fit member of the population is selected as a parent to the • probability that an average member is selected as a parent. Too high a • selection pressure will result in the population converging too early.• (Yes, higher this value, more biased to fitter chromosomes!)

Niche size:變化形 niches; 1. 壁龕2. 合適的職務 ( 或地位等 )[(+in)]You can then find your own niche in public life. 那時候你就可以在社會上找到適合自己的工作了。3. 利基vt. 及物動詞變化形 niches; 1. 把 ( 雕像等 ) 放入壁龕 [H](for keep diversity of conformations in a population!): Niching is a common technique used in genetic algorithms to preserve diversity within the population. In GOLD, two individuals share the same niche if the rmsd between the coordinates of their donor and acceptor atoms is less than 1.0 Å.When adding a new individual to the population, a count is made of the number of individuals in the population that inhabit the same niche as the new chromosome. If there are more than NicheSize individuals in the niche, then the new individual replaces the worst member of the niche rather than the worst member of the total population(don’t know when the replacement of individuals happens, but, knowing its meaning first! … typical value is 2)

In Autodock:

• ga_elitism <integer> (usually is 1)• [1]This is used in the selection mechanism of the GA. This is the

number of top individuals that are guaranteed to survive into the next generation.

• Crossover and mutation are performed on random members of the population according to user-defined rates of crossover and mutation. First, crossover is performed. Two-point crossover is used, with breaks occurring only between genes, never within a gene—this prevents erratic changes in the real values of the genes. Thus, both parents’ chromosomes would be broken into three pieces at the same gene positions, each piece containing one or more genes; for instance, ABC and abc. The chromosomes of the resulting offspring after two point crossover would be AbC and aBc. These offspring replace the parents in the population, keeping the population size constant.

Molecular Dynamics simulation

• 解牛頓方程式：

需要初始位置與速度

• 分子力場：