LSM2104CZ2251

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LSM2104/CZ2251 Essential Bioinformatics and
Biocomputing 
Protein Structure and Visualization (3)
Chen Yu Zong   csccyz_at_nus.edu.sg 6874-6877
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LSM2104/CZ2251 Essential Bioinformatics and
Biocomputing 
Lecture 11 Receptor Ligand Binding, Energy
Minimization and docking concepts Structural
Modelling
1. Receptor-Ligand Interactions 2. Energy
description of structures 3. Structure
optimization by energy minimization 4.
Receptor-ligand docking
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Protein-Protein Interaction

• Protein-Protein interaction
• Surface contact, shape complementarity
• Intermolecular forces
• Van der Waals, hydrogen bonding, electrostatic
  force

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Hydrogen Bond

• Types of Hydrogen Bond
• N-H O
• N-H N
• O-H N
• O-H O

V
r
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Protein-DNA Interaction

• Protein-DNA
• interaction
• DNA recognition by proteins is primarily mediated
  by certain classes of DNA binding domains and
  motifs

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Protein-RNA Interaction

• Protein-RNA
• interaction
• RNA recognition by proteins is primarily mediated
  by certain classes of RNA binding domains and
  motifs

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Protein-Ligand Interaction

• Ligand Binding
• A small molecule
• ligand normally binds
• to a cavity of a protein.
• Why?
• Effect of Binding
• Activate, inhibit,
• being metabolized or
• transported by,
• the protein

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Protein-Ligand Interaction

• Ligand Binding
• A small molecule
• ligand normally binds
• to a cavity of a protein.
• Why?
• Effect of Binding
• Activate, inhibit,
• being metabolized or
• transported by,
• the protein

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Protein-Ligand Interaction

• Ligand Binding
• A small molecule
• ligand normally binds
• to a cavity of a protein.
• Why?
• Effect of Binding
• Activate, inhibit,
• being metabolized or
• transported by,
• the protein

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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

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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

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Example of Binding Induced Shape Change
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Example 2 Induced Fit of Hexokinase (blue) Upon
Binding of Glucose (red).
Note that the active site is a pocket within the
enzyme.
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Energy Description

• Energy is needed to make things or objects
  change
• Movement, Chemical reaction, Binding,
  Dissociation, Structural Change,
• Conformational change etc.
• Why Energy Description for molecular structure?
• Structure determination (evolution of a
  structural-template into the correct structure)
• Binding induced shape change (binding sometimes
  induces shape change, one of the mechanisms for
  the interference of the function of a molecule by
  another)
• Protein motions (proteins undergo internal
  motions that have implications such as the switch
  between active and in-active state)

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Energy Description
Kinetic energy -- motional energy Kinetic energy
is related to the speed and mass of a moving
object. The higher the speed and the heavier the
object is, the bigger work it can do.  
Potential Energy -- "positional" energy.
  Water falls from higher ground to lower
ground. In physics such a phenomenon is modeled
by potential energy description Objects move
from higher potential energy place to lower
potential energy place.
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Potential Energy Description ofProtein Structure
Evolution

•  
• A molecule changes from higher potential energy
  form to lower potential energy form.
• Potential energy is determined by
  inter-molecular, intra-molecular, and
  environmental forces
• Protein structural evolution can be performed
  by systematic variation of the atom positions
  towards the lower energy directions. This
  procedure is called structure optimization or
  energy minimization

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Energy Minimization for Structural Optimization

•  
• Protein structure evolution can be performed by
  systematical variation of the atom positions
  towards the lower energy directions. This
  procedure is called structure optimization or
  energy minimization

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Potential Energy Surface (PES)

• A force field defines for each molecule a unique
  PES.
• Each point on the PES represents a molecular
  conformation characterized by its structure and
  energy.
• Energy is a function of the coordinates.
• (Next) Coordinates are function of the energy.

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Goal of Energy Minimization

• A system of N atoms is defined by 3N Cartesian
  coordinates or 3N-6 internal coordinates. These
  define a multi-dimensional potential energy
  surface (PES).

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Classification of Stationary Points

• Refers to the eigenvalues of the second
  derivatives (Hessian) matrix

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Minimization Definitions

• Given a function
• Find values for the variables for which f is a
  minimum

• Functions
• Quantum mechanics energy
• Molecular mechanics energy
• Variables
• Cartesian (molecular mechanics)
• Internal (quantum mechanics)
• Minimization algorithms
• Derivatives-based
• Non derivatives-based

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A Schematic Representation
Starting geometry

• Easy to implement useful for well defined
  structures
• Depends strongly on starting geometry

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Population of Minima
Active Structure
Most populated minimum
Global minimum

• Most minimization method can only go downhill and
  so locate the closest (downhill sense) minimum.
• No minimization method can guarantee the location
  of the global energy minimum.
• No method has proven the best for all problems.

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A General Minimization Scheme
Starting point x0
yes
Minimum?
Stop
No
Calculate xk1 f(xk)
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Two Questions

• Where to go (direction)?
• How far to go (magnitude)?

This is where we want to go
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How Far To Go? Until the Minimum
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Steepest Descent

• Where to go?
• Parallel to the force (straight downhill) Sk
  -gk
• How far to go?
• Line search
• Arbitrary Step

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Steepest Descent Example
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Steepest DescentOvershooting

• SD is forced to make 90º turns between subsequent
  steps (the scalar product between the (-18,-36)
  and the (-8,4) vector is 0 indicating
  orthogonality) and so is slow to converge.

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Why Ligand-Protein Docking?

• Molecular recognition is a central phenomenon in
  biology
• Enzymes ? Substrates
• Receptors ? Signal inducing ligands
• Antibodies ? Antigens

• Classifying docking problems in biology
• Protein-ligand docking
• Rigid-body docking
• Flexible docking
• Protein-protein docking
• Protein-DNA docking
• DNA-ligand docking

• Ligand-Protein Docking
• Proteins ? Drugs
• Proteins ? Natural Small Molecule Substrates

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The Molecular Docking Problem
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Basic Principles

• The association of molecules is based on
  interactions
• H-bonds, salt bridges, hydrophobic contacts,
  electrostatic
• Very strong repulsive (VdW) interactions on short
  distances.
• Association interactions are weak and short
  ranged.
• Strong binding implies surface complementarity.
• Most molecules are flexible.

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Docking Concept
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Representation of a Cavity

• HIV-1 Protease

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Generation of Cavity Model
Molecular surface model at active site
Active site filled with spheres. Sphere centers
become potential locations for ligand atoms.
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• Ligand-protein docking concept

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.

• Ligand-protein docking concept

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Ligand-Protein Docking Concept
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Checking Chemical Complementarity in
Ligand-Protein Docking

• Potential Energy Between Ligand and Protein

• A ligand with sufficiently low ligand-protein
  potential energy is considered as a drug
  candidate
• Chemical database can be searched to find which
  chemical molecules can be docked to a disease
  protein with sufficiently low ligand-protein
  energy

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Summary

• Receptor-ligand binding
• Energy minimization for structural optimization
• Receptor-ligand docking concept