Jan 16, 2016
COMPUTATIONAL VACCINOLOGY
SUBUNITVACCINE
EPITOPEVACCINE
Vaccines induce protective immunity, an enhanced adaptive immune response to re-infection.
WHOLEORGANISM
World classdatabase
Antigens,B cell and T cell
epitopesPeptide binding,Protein-Protein
Interactions
ImprovedPrediction
Class I and IIT cell epitope
prediction
B cell epitopesand Antigens
Experimentalverification
and data discovery
test predictionand generate
new binding data
COMPUTATIONAL VACCINOLOGY
TCR, MHC and co-receptors on the surface of T-cell and antigen-presenting cell.
T-cells have T cell receptors in their membranes that bind to the protein fragments presented by the MHC proteins.
T cells recognise the presence of foreign protein and hence pathogenic micro-organisms and then destroy them.
T-cell, TCR and MHC
Peptide MHC binding is just like the binding of drugs to other receptors
We can use QSAR and molecular dynamics (MD) simulation to examine, model and predict MHC-peptide interaction
TCR-peptide-MHC complex
DATA DRIVENMODELLING:
QSAR
Irini Doytchinova
Channa HattutawagamaValerie WalshePingPing Guan
QSARQUANTITATIVE STRUCTURE
ACTIVITY RELATIONSHIP
STRUCTURALDESCRIPTION
andBIOLOGICAL
RESPONSE
ROBUSTMULTIVARIATE
STATISTICS
PREDICTIVEQSAR
MODEL
+ IC50spIC50 exp
pIC5
pred
Y=X*W*(P’*W)-1*C’+F
CoMSIA model
5
6
7
8
9
5 6 7 8 9
experimental pIC50
r = 0.783
pred
icte
d pI
C50
CoMFA model
5
6
7
8
9
5 6 7 8 9
experimental pIC50
r = 0.694
pred
icte
d pI
C50
Training set102
peptides
Test set50
peptides
152 peptideswith affinity tothe HLA-A2.1
Training set102
peptides
Test set50
peptides
152 peptideswith affinity tothe HLA-A2.1
r2pred < 0.5
NC = 6 q2 = 0.480 r2 = 0.911
r2pred = 0.679
NC = 5 q2 = 0.542 r2 = 0.870
Comparison ofCoMFA and CoMSIA
for HLA-A*0201
Hydrophobic Map
Hydrogen Bond Map
Steric Map
Electrostatic Map
NC = 7 q2 = 0.683 r2 = 0.891 n = 236
Full CoMSIA Analysis of HLA-A*0201
HN
N
H O
H
NN
N
O
H O
H O
NN
N
H O
H O
H O
H
N
O
H OH
O
P1
P2
P3
P4
P5
P6
P7
P8
P9
2i
7
1ii1i
8
1ii
9
1ii50 PPPPPconstpIC
HLA-A*0201: NC = 5 q2 = 0.337 r2 = 0.898 n = 340
ADDITIVE METHOD FOR AFFINITY PREDICTION
STRUCTURE DRIVENMODELLING:ATOMISTIC
MOLECULAR DYNAMICSIMULATION
Shunzhou Wan
DESIGN MUTANTS
Point MutantsChimeras
Deletion Mutants
Fusion Proteins
PREDICT
DYNAMIC PROPERTIES
Molecular Dynamics Simulations
PREDICT LIGANDS
Small Molecule DockingDrug Design
PREDICT
PROTEIN - PROTEIN
INTERACTIONS
Large Molecule Docking
ANTIBODYBINDING
MHC-peptide BINDING
PREDICTTHERMODYNAMICS
OF BINDING
PREDICTCOMPLEX
BEHAVIOUR
High Performance Computing& Biomolecular Simulations
Simulations of Biomolecular Systems includeproteins, nucleic acids, drug-receptor interactions,
protein folding, and a few examples of more complex systems, such protein-membrane interactions.
Most simulations done on desktop workstations and “small” parallel machines (~32 processors)
Long time scales and large systems generally intractable
HPC and the GRID allow us, for the first time, to do things properly
Simulated systems are LARGE: 30,000-300,000 atoms
Simulation timescales are LONG: In nanoseconds, even microsecond1
Requires high performance computing
We use scalable codes LAMMPS (Large-scale Atomic/Molecular Massively Parallel Simulator) & NAMD
on large parallel machines (up to 1000+ nodes)
Large Scale Molecular Dynamics
1. Duan Y, et al., Science 1998, 282:740-744.
MD scaling performance (LAMMPS)
Parallelising the AMBER software scales very poorly in our hands
MHC-peptide complexes
HLA-A*0201:MAGE-A4 complex
Simulated using AMBER force field in LAMMPS
a)
…
1- 2 domainsperiodic boundaryno constraints
Rognan et al. (1992) Proteins 13, 70-85
b) c)
1- 2 domainsperiodic boundaryconstraints on backbone
Meng et al. (1997) Int. Immunol. 9, 1339-1346
all domainsspherical boundaryfix all atoms out of sphereconstraints on outer buffer region of sphere
Michielin et al. (2002) J. Mol. Biol. 324, 547-569
MHC-peptide complexes: What has been done?
Can the a3 and b2m domains
and/or their movement
be neglected in simulations?
MHC-peptide complexes
MHC-peptide complexes: Simulation models
Partial model30,574 atomsNo constraints
Full model58,825 atomsNo constraints
Many authors1 regards this system as being out of reach of MD simulation
- "much too large"
- "relevant time scales inaccessible"
But, with scalable codes and tightly coupled massively parallel machines ...
1. Nojima et al., Chem Pharm Bull (Tokyo) 2002 50(9), 1209-1214.
Amber 98 Force Field
MHC-peptide complexes: Simulation models
... for the 58,825 atom
model (whole model),
we can perform 1 ns
simulation in 17 hours'
wall clock time on 256
processors of Cray T3E
using LAMMPS
MHC-peptide complexes: Results
For the partial
system, about 300ps
were required for
equilibration, while
the whole system
required about
600ps, equilibration
here being a function
of the size of the
system. RMS deviation from x-ray structure versus simulation time (ps). Above: partial MHC-peptide system; Below: whole MHC-peptide system. Solid line: mainchain of protein; Dotted line: mainchain of peptide.
MHC-peptide complexes: Results
In the partial system simulation, the middle sheets (4, 5) at the bottom of groove bulge towards the peptide, while 1, 2 and 8 turn aside from it, whereas the whole system simulation does not exhibit these effects.
View of the b-sheets of the average structures from the partial system simulation (blue) and the whole system simulation (yellow), compared with the x-ray structure (red). From top to bottom, the sheets are juxtaposed from the N-terminal to the C-terminal of the peptide. The view is directly onto the peptide-binding side.
MHC-peptide complexes: Results
The loop regions have large deviations from the x-ray structure, while the two long helices and the -sheets have relatively small deviations.
RMS deviations of peptide (top) and
antigen-binding site of MHC protein
(bottom) from x-ray structure. Solid line:
whole system simulation; Dashed line:
partial system simulation.
Peptide Fluctuation vs Thermal B-Factor
B FACTOR
The larger deviations observed with the peptide in the partial system indicate that the peptide is considerably less tightly bound in the partial system than in the whole system.
MHC-peptide complexes: Conclusions
For 58,825 atoms system, 1 ns simulation can be performed in 17 hours'
wall clock time on 256 processors of T3E.
More accurate results are obtained by simulating the whole complex
than just a part of it.
The 3 and 2m domains have a significant influence on the structural
and dynamical features of the complex, which is very important for
determining the binding efficiencies of epitopes.
We are now doing TCR-peptide-MHC simulations
(~ 100,000 atom model) using NAMD.
WE WANT USE MD TO ADDRESS FUNDAMENTAL PROBLEMS IN IMMUNOLOGY
MHCs are polymorphic – there are hundreds of individual alleles with in the human population
each with a different peptide binding specificity
Use MD to identify binding epitopes anduse these to design and develop novel vaccines
Also want to use MD to examine more complex systems such as the Immunological Synapse
which are not accessible to direct experimental analysis
Bioinformatics Group
Irini DoytchinovaShunzhou Wan
Helen McSparronValerie WalshePingPing GuanMartin BlytheDebra Taylor
EJIVR
Seph Borrow
Outside
Peter Coveney (UCL)
ACKNOWLEDGEMENTS
Funding from EPSRC (RealityGrid, CSAR)
Jenner Institute (GSK, BBSRC, MRC, DOH)