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Brennan Ferguson Greg Salazar
Advisor: Dr. Kevin Riley
Department of Chemistry, Xavier University of Louisiana
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Introduction
Theory
Methods
Results
Conclusion
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Liver X Receptor Nuclear Receptor
Forms heterodimer with Retinoid X Receptor (RXR)
α and β isoforms α is found in Liver
β is expressed everywhere
Binds to Cholesterol Derivatives
Induces Reverse Cholesterol Transport (RCT)
3IPU LXRα
1P8D LXRβ
http://www.jpp.krakow.pl/journal/archive/12_08_s7/articles/03_article.html
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Binding Pocket Large Hydrophobic Pocket
Highly Conserved Ligand Binding Doman (LBD)
Flexible
One Amino Acid Difference
Binding Pocket Difference: LXRα: Valine LXRβ: Isoleucine
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Goal: Investigate Ligand Selectivity
24(s),25-EpoxyCholesterol (EC)
5,6-24(s),25-DiEpoxyCholesterol (DEC)
DEC is LXRα selective.
O
OHO
O
OH
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Question: What determines selectivity? Protein Geometry or Ligand Interaction
Computational investigations using Molecular Operating Environment (MOE)
Docking
Molecular Dynamics
Glycine Scanning
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Ligand-Protein Interactions
Study Geometry of Complex
Find Binding Mechanism
Design selective drugs
Fight Cancer!
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Docking – holds receptor static, not helpful
Induced Fit Docking – allows receptor movement
Scores lowest binding energy (kcal/mol)
Generates Poses, scored by lowest energy state
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Molecular Dynamics Simulate movement
Multiple Poses
Computationally expensive
Sensitive to Systems with High Degrees of Freedom
Glycine Scanning What individual amino acids contribute to binding?
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Induced Fit Docking
1. Placement
Alpha Triangle – random
Triangle Matcher – slightly systematic
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2. Scoring Lower Scores Indicate more favorable poses
London dG Scoring Estimates ΔGbind of Ligand/Receptor from Pose
c is average gain/loss of rotational & translation entropy
ΔEflex is energy lost due to flexibility of ligand
ΔD is the desolvation energy of an atom
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2. Scoring GBVI/WSA Scoring
Estimates from given poses
c is average gain/loss of rotational & translation entropy
α and β are constants; force field dependent
ΔEcoul is the coulombic electrostatic term,
ΔEsol is the energy contributed by solvent
ΔEvdw is the van der Waals contribution to binding
SA is surface area weighted by exposure
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3. Refinement Relaxes Strain in System
4. Output S Value: Final Score to indicate binding free energy
Minimizes Energy through
Changes in bond angles
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Molecular Dynamics (MD) Energy Minimization Simulates Molecular Movement
Multiple Changes In Bond Angle
Relieves Strain
Highly Strained
Third Dimension Holds Energy
Still Rotates
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System Minimized Fourth Dimension allows further ΔU minimization
Step-Wise Optimization
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MD Parameters Solvation
Introduce a solvent sphere within 4 Ȧ radius of protein
Equilibrate Hold time still, minimize system at a given temperature
Production Isothermal & Isochoric
Simulates Molecular Movement for t picoseconds (ps)
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Molecular Dynamics
Nosé-Poincaré-Andersen (NPA) equations of motion
Utilizes, scaled-space coordinates, real space coordinates, real spaced momenta to describe movement.
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Glycine Scanning Determination of Relative Binding Contribution
Changes Native Amino Acids Glycine (R=H)
Re-Score the Mutated Protein
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Obtained Crystal Structures from Protein Data Bank
3IPU – LXRα
IP8D - LXRβ
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Filled in gaps in crystal structure
Fixed charges
Protonated
Minimized
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Defined the active site
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Built:
EC
DEC
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Used Induced Fit docking to dock EC and DEC to LXRα and LXRβ
Placement: Triangle Matcher
Rescoring 1: London dG
Refinement: Force field: AMBER99
Rescoring 2: GBVI/WSA dG
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Minimized the poses with the 5 lowest S-values
Re-scored poses; Static Receptor + Ligand GVI/WSA Scoring Algorithm
Non-minimized Minimized
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Top poses were aligned to compare
Green-1P8D Blue-3IPU
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Ran dynamics for top docking poses in solvent
Time step 0.002 ps
Equilibrium stage 100 ps
Used Nosé-Poincaré-Andersen (NPA) equations of motion
Simulated for 500 ps
Total time 600 ps
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Glycine scanning for best docked poses and snapshots from dynamics:
LXRα – EC
LXRα – DEC
LXRβ –EC
LXRβ –DEC
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Used 2-D interaction map to find amino acid/ligand interactions
Individually mutated amino acid to Glycine and then Re-scored
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-10.7
-10.65
-10.6
-10.55
-10.5
-10.45
-10.4
-10.35
-10.3
-10.25
S-v
alu
e (
kca
l/m
ol)
Docking S-value
LXRβ-EC
LXRβ-DEC
LXRα-EC
LXRα-DEC
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100 150 200 250 300 350 400 450 500 550 600
-110
-105
-100
-95
-90
-85
-80
-75
-70
Time (ps)
Inte
ra
cti
on
En
erg
y (
kca
l/m
ol)
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Potential Interaction Energy
100 150 200 250 300 350 400 450 500 550 600
-110
-105
-100
-95
-90
-85
-80
-75
-70
Time (ps)
Inte
ract
ion
Ene
rgy
(kca
l/mol
)
5,6-24(s),25-DEC LXRα
100 150 200 250 300 350 400 450 500 550 600
-110
-105
-100
-95
-90
-85
-80
-75
-70
Time (ps)
Inte
ra
cti
on
En
erg
y (
kca
l/m
ol)
5,6-24(s),25-DEC LXRβ
100 150 200 250 300 350 400 450 500 550 600
-110
-105
-100
-95
-90
-85
-80
-75
-70
Time (ps)
Inte
racti
on
En
ergy (
kcal/
mol)
24(S),25-EC LXRβ
100 150 200 250 300 350 400 450 500 550 600
-110
-105
-100
-95
-90
-85
-80
-75
-70
Time (ps)
Inte
ra
cti
on
En
erg
y (
kca
l/m
ol)
24(S),25-EC LXRα
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Snapshot Re-score
100 200 300 400 500 600
-14
-13
-12
-11
-10
-9
-8
Time (ps)
S-v
alu
e (
kcal/
mol)
Dynamics
LXRα-EC
LXRα-DEC
LXRβ-EC
LXRβ-DEC
Convergence
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Web of hydrogen bonds
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Significant amino acids
Gln 246
Asn 239
Glu 281
Ile 353
Leu 313
Met 312
Phe 243
Phe 349
Val 439
Wild Type
-10.8
-10.7
-10.6
-10.5
-10.4
-10.3
-10.2
-10.1
-10.0
S-v
alu
e (k
cal/
mol)Glycine Scan for EC
LXRβ-EC
LXRα-EC
Noticeable Difference
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Gln 246 His 435 Ile 309 Ile 353 Phe 243 Phe 340
Wild Type
-10.8
-10.7
-10.6
-10.5
-10.4
-10.3
-10.2
-10.1
-10.0S
-valu
e (
kcal/
mol)
Glycine Scan for DEC
LXRβ-DEC
LXRα-DEC
Tiny Difference
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Phe 229 (LXRα - cyan) and Phe 243 (LXRβ - green)
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Docking – inconclusive because isoforms have similar binding affinity for DEC
Dynamics – LXRβ has slightly higher affinity for DEC than LXRα for DEC
LXRβ looses affinity over time
Glycine Scanning – different orientation and binding influence of Phe 229 (LXRα) and Phe 243 (LXRβ )
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Optimize parameters for docking
Run Dynamics for longer periods
Study LXRβ selective ligands
Simulate analogs of LXRβ selective ligands
Study kinetic binding mechanism for complex
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Dr. Riley
LA-SiGMA REU
NSF
Xavier University
Dr. Sridhar
Sydni Bellow
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Viennois, E., et al. Selective liver X receptor modulators (SLiMs): What use in human health? Mol. Cell. Endocrinol. 2012, 351, 129-141
Hiranthi, J., et al. Diterpenoid, steroid, and triterpenoid agonists of liver X receptors from diversified terrestrial plants and marine sources. J. Nat. Prod. 2005, 68, 1247-1252.
Janowski, B., et al. Structural requitements of ligands for the oxysterol liver X receptors LXRα and LXRβ. Proc. Natl. Acad. Sci. 1999, 96, 266-271.
Haung, T., et al. A novel LXR-α activator identified from the natural product Gynostemma pentaphyllum. Biochem. Pharmacol. 2005, 70, 1298-1308.