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Knowledge-based scoring functions

Knowledge-based scoring functions are derived from a statistical analysis of structures of protein-ligand complexes in the RCSB Protein Databank (PDB). Searches are made for each possible pair of atoms in contact with each other. Interactions found to occur more frequently than would be predicted by random chance are considered attractive (stabilizing), and interactions that occur less frequently are considered repulsive (destabilizing). Examples of knowledge-based scoring functions include Muegge’s Potential of Mean Force function [3] and DrugScore [4] .

Rigid receptor docking

Parameterization of the problem

Many docking algorithms make the simplifying, but potentially quite inaccurate, assumption that the receptor is a rigid object and attempt to dock the ligand to it. The receptor conformation used is generally one from a receptor-ligand complex whose structure has been determined by x-ray crystallography or NMR spectroscopy. Because the receptor cannot move, the degrees of freedom of the problem are those of the ligand: three translational, three global-rotational, and one internal dihedral rotation for each rotatable bond. It is generally assumed that bond lengths and the angles formed by adjacent bonds do not change, and on the scale of most ligands (10 to 40 atoms), this assumption is a reasonable one. Docking to a rigid receptor is thus an optimization problem over a 6 + n dimensional space, where n is the number of rotatable bonds in the ligand.

Examples of rigid-receptor docking programs

Autodock 3.0

Autodock is actually a set of closely related programs and algorithms developed at the Scripps Research Institute and the University of California at San Diego.

Search technique

Autodock can use one of several optimization methods to search for the best placement of the ligand:

  • Simulated annealing: At each step of simulated annealing, the position and internal rotational state of the ligand is adjusted and the energy calculated. If the energy decreases, the move is accepted. If not, it may be accepted with some probability that depends on the current temperature of the annealing. As the search goes on, the temperature is decreased, and eventually, the final state of the ligand is returned as the docked conformation. Because simulated annealing is a Monte Carlo (randomized) method, different runs will generally produce different solutions.
  • A genetic algorithm: The genetic algorithm represents the states of the degrees of freedom of the ligand as a string of digits, and this string is referred to as a gene. A population of different genes is generated at random, and each is scored using the Autodock energy function. Genes are selected to form the next population based on their score, with better scoring genes more likely to be selected. A gene may be selected more than once, and some may not be selected at all. Pairs of the selected genes are allowed to cross over with each other. In this process, a segment of the gene is selected and the values in this range are exchanged between them. The hope is that by combined two partially good solutions, we will eventually find a better solution.
  • a Lamarckian genetic algorithm (LGA): This is the same as the standard genetic algorithm except that, before they are scored, each conformation (gene) is subjected to energy minimization. The next population is then founded by members of this energy-minimized population. The name "Lamarckian" refers to the failed genetic theory of Jean-Baptiste Lamarck, who held that an organism could pass on changed experienced in its lifetime to its offspring. This theory was eventually abandoned in favor of Mendel's now-familiar laws of inheritance. The LGA is faster than both simulated annealing and the standard genetic algorithm, and it allows the docking of ligands with more degrees of freedom.

Questions & Answers

show that the set of all natural number form semi group under the composition of addition
Nikhil Reply
what is the meaning
Dominic
explain and give four Example hyperbolic function
Lukman Reply
_3_2_1
felecia
⅗ ⅔½
felecia
_½+⅔-¾
felecia
The denominator of a certain fraction is 9 more than the numerator. If 6 is added to both terms of the fraction, the value of the fraction becomes 2/3. Find the original fraction. 2. The sum of the least and greatest of 3 consecutive integers is 60. What are the valu
SABAL Reply
1. x + 6 2 -------------- = _ x + 9 + 6 3 x + 6 3 ----------- x -- (cross multiply) x + 15 2 3(x + 6) = 2(x + 15) 3x + 18 = 2x + 30 (-2x from both) x + 18 = 30 (-18 from both) x = 12 Test: 12 + 6 18 2 -------------- = --- = --- 12 + 9 + 6 27 3
Pawel
2. (x) + (x + 2) = 60 2x + 2 = 60 2x = 58 x = 29 29, 30, & 31
Pawel
ok
Ifeanyi
on number 2 question How did you got 2x +2
Ifeanyi
combine like terms. x + x + 2 is same as 2x + 2
Pawel
x*x=2
felecia
2+2x=
felecia
×/×+9+6/1
Debbie
Q2 x+(x+2)+(x+4)=60 3x+6=60 3x+6-6=60-6 3x=54 3x/3=54/3 x=18 :. The numbers are 18,20 and 22
Naagmenkoma
Mark and Don are planning to sell each of their marble collections at a garage sale. If Don has 1 more than 3 times the number of marbles Mark has, how many does each boy have to sell if the total number of marbles is 113?
mariel Reply
Mark = x,. Don = 3x + 1 x + 3x + 1 = 113 4x = 112, x = 28 Mark = 28, Don = 85, 28 + 85 = 113
Pawel
how do I set up the problem?
Harshika Reply
what is a solution set?
Harshika
find the subring of gaussian integers?
Rofiqul
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Shirley Reply
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Abdullahi
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Mark
I need quadratic equation link to Alpa Beta
Abdullahi Reply
find the value of 2x=32
Felix Reply
divide by 2 on each side of the equal sign to solve for x
corri
X=16
Michael
Want to review on complex number 1.What are complex number 2.How to solve complex number problems.
Beyan
yes i wantt to review
Mark
16
Makan
x=16
Makan
use the y -intercept and slope to sketch the graph of the equation y=6x
Only Reply
how do we prove the quadratic formular
Seidu Reply
please help me prove quadratic formula
Darius
hello, if you have a question about Algebra 2. I may be able to help. I am an Algebra 2 Teacher
Shirley Reply
thank you help me with how to prove the quadratic equation
Seidu
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Opoku
what is math number
Tric Reply
4
Trista
x-2y+3z=-3 2x-y+z=7 -x+3y-z=6
Sidiki Reply
can you teacch how to solve that🙏
Mark
Solve for the first variable in one of the equations, then substitute the result into the other equation. Point For: (6111,4111,−411)(6111,4111,-411) Equation Form: x=6111,y=4111,z=−411x=6111,y=4111,z=-411
Brenna
(61/11,41/11,−4/11)
Brenna
x=61/11 y=41/11 z=−4/11 x=61/11 y=41/11 z=-4/11
Brenna
Need help solving this problem (2/7)^-2
Simone Reply
x+2y-z=7
Sidiki
what is the coefficient of -4×
Mehri Reply
-1
Shedrak
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Source:  OpenStax, Geometric methods in structural computational biology. OpenStax CNX. Jun 11, 2007 Download for free at http://cnx.org/content/col10344/1.6
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