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Peeking into the heart of new Cresset science · 2019-06-25 · Protein interaction potentials...
Transcript of Peeking into the heart of new Cresset science · 2019-06-25 · Protein interaction potentials...
Peeking into the heart of new Cresset scienceMark Mackey
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Overview
> New science in Flare
> Protein interaction potentials
> 3D-RISM
> WaterSwap
> Lead Finder
> Ongoing collaborations
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Protein interaction potentials
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Protein interaction potentials
Reveal the hidden
electrostatic character of
protein binding sites
Compare related
proteins to identify
selectivity opportunities
Understand SAR trends and ligand
binding from the protein’s perspective
Inform ligand design
through use of protein
electrostatics
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> Basic idea is the same as ligand
field
> Field value is the computed interaction
energy with a charged probe, using
XED
> Field surfaces found to be more useful
than field points
> XED force field electrostatics
emphasizes signal from aromatic
residues
> Visual method at this stage – no
scoring
> Challenges
> Solvation
> Use modified dielectric function
> Screened Coulombic Potential model of
Mehler et al.
Protein interaction potentials - Challenges
Mehler, E. L., in “Molecular Electrostatic Potentials:
Concepts and Applications” pp371-405
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SCP model
0
10
20
30
40
50
60
70
80
0 2 4 6 8 10 12 14 16 18 20
D(r
)
r (Å)
SCP dielectric function
0.1
1
10
100
1000
0 2 4 6 8 10 12 14 16 18 20
E/q
q (
kcal/m
ol)
r (Å)
Coloumbic energy
D(r) D=1 D=78
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> Basic idea is the same as ligand
field
> Field value is the computed interaction
energy with a charged probe, using
XED
> Field surfaces found to be more useful
than field points
> XED force field electrostatics
emphasizes signal from aromatic
residues
> Visual method at this stage – no
scoring
> Challenges
> Solvation
> Use modified dielectric function
> Screened Coulombic Potential model of
Mehler et al.
> Protein Prep
> PIPs are highly sensitive to where the
hydrogens are!
> Build Model (BioMolTech)
Protein interaction potentials - Challenges
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PIP example – 4M7I (PERK)
= Positive = Negative
Protein Electrostatics - Dry
Contour 3 Kcal/mol
Ligand Electrostatics
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Adding crystal water to the calculation of protein electrostatics
Contour 3 Kcal/mol
Protein Electrostatics – with crystallographic water Ligand Electrostatics
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> TSAR algorithm (thermodynamic
sampling of amino acid residues)
Build Model
Proteins, 2011, 79, 2693-2710
Validated by
prediction of
experimentally-
measured amino
acid pKa values
Interaction graph
treated as a belief
network, and solved
for the partition
function for each node
The state of K99
depends on the
state of Y93, as
they interact with
each other
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Using PIPs to explain SAR
negativeTNNI3K 7.3; bRaf 6 TNNI3K 7.5; bRaf 6.2 TNNI3K 7.1; bRaf 6
TNNI3K 6.7; bRaf 6.6 TNNI3K 6.4; bRaf 6.4 TNNI3K 5.6; bRaf 5.2
11.0 10.511.2
10.5 9.310.1
4 3.24.5
3.4 1.52.8
y = 0.8853x + 5.0458R² = 0.9428
9.8
10
10.2
10.4
10.6
10.8
11
11.2
11.4
11.6
11.8
5 5.5 6 6.5 7 7.5 8
Edge Field size vs TNNI3K activity
No correlation for bRaf – why?
Lawhorn et al. J. Med. Chem. 2016, 59, 10629−10641
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Selectivity - TNNI3K vs B-Raf
Lawhorn et al. J. Med. Chem. 2016, 59, 10629−10641
TNNI3K B-Raf
Ring in +ve PIP, so e-
donating goodRing in -ve PIP, so e-
donating bad
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3D-RISM – water position and stability
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3D-RISM
> Analytical method for working out where water goes (Ornstein-Zernike equation)
> Conceptually equivalent to running an infinite-time MD simulation on the solvent and extracting the solvent particle densities
ℎ 𝑟12 = 𝑐 𝑟12 +න𝑑𝑟3𝑐 𝑟13 𝜌 𝑟3 ℎ(𝑟23)
Total correlation
function
'What is the
distribution of solvent
around the solute?'
Direct correlation
function
'How does a solvent
molecule interact with
the solute?'
Indirect influence through all possible
chains of mediating third particles
'What is the effect of a solvent
molecule interacting with another
solvent molecule which is interacting
with the solute?'
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3D-RISM
> Analytical method for working out where water goes (Ornstein-Zernike equation)
> Conceptually equivalent to running an infinite-time MD simulation on the solvent and extracting the solvent particle densities
> Output is grid containing particle densities (for water, O and H densities)
> Thermodynamic analysis to assign 'happiness' to each position on the grid
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Limitations
> Fixed solute> No accounting for protein movement
> Can’t solve equations exactly> Need to use a 'bridge function' – unclear what the correct functional form is
> Results depend on the interaction potential U(r) used by the closure function> In practise, this means vdW + electrostatics
> Results only as good as your potential functions
> Need to pay attention to total formal charge of the system
> An improved description of electrostatics will give better results!
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How to compute RISM water G values?
> Raw output from RISM calculation is density and G grids for H
and O
Place oxygen on highest-
density grid point
O H
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How to compute RISM water G values?
> Raw output from RISM calculation is density and G grids for H
and O
O H
Compute G by
integrating G
grids on atomic
volumes
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How to compute RISM water G values?
> Raw output from RISM calculation is density and G grids for H
and O
O H
Repeat with multiple
orientations and
small translations
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How to compute RISM water G values?
> Raw output from RISM calculation is density and G grids for H
and O
O H
Final G estimate is
weighted average of
the MC samples
(weighted by the
product of the O and
H density values)
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3D RISM example - 4ZLZ (BTK)
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RISM calculation on 4ZLZ
> Bridging water correctly placed
> Computed G is very slightly
favourable
> Water is displaceable, but you need to
match it pharmacophorically
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Calculate 3D-RISM for bridging water molecule
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WaterSwap – ligand energetics
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> WaterSwap uses a λ-coordinate to swap a ligand and a water cluster
between a protein box and a water box
WaterSwap - Method
Water box Protein box Protein box Water box
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Parallel calculation of WaterSwap results
> WaterSwap calculations are compute-intensive
> MC simulations are not amenable to distributed computing or
GPGPUs
> Runs on one machine – speed determined by number of cores
> Can we get sufficient sampling by combining independent runs?
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Ongoing collaborations
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> Accurate pose prediction and detailed scoring> See new molecule designs within the
cavity of your protein target
> Accurate pose prediction
> Detailed scoring function
> Flexible deployment
% Correct pose prediction Top 10 Top 3 Top 1
Build model and Lead Finder 88 86 82
Performance on the Astex diverse set with success counted only if the RMSD
between X-ray and docked ligand was less than 2.0Å in 5 or more of 10 runs
Lead Finder (BioMolTech)
Lead Finder successfully finds the correct ligand
position (sticks) with 1.2Å RMSD from an X-ray
structure (electron density as mesh) in this difficult
HIV-1 protease example
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Lead Finder
Lead Finder successfully finds the correct ligand
position (sticks) with 1.2Å RMSD from an X-ray
structure (electron density as mesh) in this difficult
HIV-1 protease example
> Template docking
> Fast docking with constrained poses
> Field-guided docking
> Combine ligand and protein information
> Improved ring sampling
> Use the XedeX ring library from the
CSD to improve ring sampling
> XED electrostatics
> Use the XED force field electrostatics
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Working with the best academic and commercial science
> WEGA (iPrecision Medicine)
> Improved Gaussian shape similarity
> CPU + GPU
> Aim to launch a shape similarity tool in
2017
> Others
> Ongoing or upcoming collaborations
with ICL, Sheffield, TMCS etc.
> XED improvements
> Adding metal support to the XED force
field
> General parameter improvements
> BioSimSpace
> Collaboration between Edinburgh,
Bristol, UCL, and Nottingham
> Develop workflow components for
molecule design
> Cresset is the commercial partner