Transcript Docking Algorithms Flow

CAPRI
Critical Assessment of Prediction
of Interactions
CAPRI docking targets
• CAPRI-01 (unbound/unbound) Lactobacillus HPr kinase B. subtilis HPr
• CAPRI-02 (unbound/bound) bovine rotavirus VP6 - Fab
• CAPRI-03 (unbound/bound) flu hemagglutinin - Fab HC63
Docking Algorithms Flow
Molecular Surface
representation
Active site
knowledge
Critical points
selection
Matching of
critical points
Clustering and
Scoring
Molecular Surface Representation
Budda
• Connoly surface for
grid distance function
calculations
• Shuo points as critical
points
Kely
• Connoly surface as
critical points
Critical Points Selection
Budda
• Volume function is
computed for each
shuo point and knobs
and holes are selected.
Kely
• Volume function is
computed for each
point and local
minimum and
maximum of knobs
and holes are selected.
Matching of Critical Points
Both algorithms use Pose-Clustering technique:
• For each triangle of receptor compute the
transformation to each ligand matching triangle.
• Cluster transformations.
• Score the results.
Complexity: O(m3n3)
Reference Frame Selection
Budda
• Each reference frame is
defined by one critical
point (knob, hole) and two
it’s neighbors.
• The signature includes
triangle sides length, the
angles a1, a2 and torsion
angle w for AB and AC.
Kely
• Each reference frame is
defined by 2 points
(knobs,holes) and their
normals.
• The signature information
includes the distance between
two points, the angles a1, a2
and torsion angle w.
B
A
w
C
a1
a2
Reference Frame Complementarity
Budda
• Knob matches hole for one
point only, not necessary for
neighbor points.
• The difference between
distances (AB,AC,BC) < d_thr.
• The difference between the
angles < angle_thr.
Complexity: O(m3n3)
B
Kely
• Knob matches hole for every
point.
• The difference between
distances < d_thr.
• The difference between the
angles < angle_thr.
Complexity: O(m2n2)
w
a1
A
C
a2
Clustering
Budda
• At first fast clustering
by transformation
parameters is
performed.
• For final results, the
RMSD clustering on
the interface is
applied.
Kely
• The transformations
are clustered by the
rotational angle
between every two
conformers.
Geometric Scoring
Budda
• A number of ranges on the
surface of receptor molecule is
defined:
• Only 3 ranges are used:
< -2 |-2:-1.5|-1.5:-1| -1:1 |1:1.5| >1.5
• The score is given as:
• For each interface number of
surface (shuo) points in each
range is computed.
• The score is a weigted function
of each layer.
• In addition, number of
penetrating residues is
computed and added to the
score.
Kely
Surface, Exterior, Core.
GS=S-4E-C2/(1+e6-C)
• Additional geom. score:
NS = GS/S
• Electrostatic “clashes” filter
• Connected components of
interface filter.
Capri1: enzyme – inhibitor
• HPr kinase/phosphatase is a key regulatory
enzyme controlling carbon metabolism in bacteria.
• The protein is a hexamer.
• HprK/P contains the Walker motif - characterisctic
of nucleotide-binding proteins
Capri1: enzyme – inhibitor
Capri1: enzyme – inhibitor
• It catalyses the ATP-dependent
phosphorelation/dephosphorelation of Ser46 in
HPr.
Capri1: enzyme – inhibitor
• The docking was done using Walker motif and
Ser46 as active site, so that only relevant solutions
could be created.
• The filter on the
distance between
phosphate and
oxygen atoms of Asp
was applied. Only
relevant solutions
were selected.
Capri 2 and Capri3- biology
background
• Viral capsid:
biology background …
• Capri2 - VP6 protein of rotavirus that
causes gastroenteritis in children.
• Capri3 – influenza hemagglutinin.
Capri 2
Capri2 antigen ...
• Trimmer. (symmetry)
• The surface of the B (helices) domain is buried in
rotavirus capsid.
• The H-domain interacts with the antibody.
• A ‘hint’ was given- to use the trimmer in the
docking, meaning that active site is expanded to
more than one chain.
Capri 3
Capri3 antigen ...
• Hexamer. 3 dimmers (symmetry)
• One chain of the dimmer(s) is buried in the capsid
• Other antibody-antigen complexes of this antigen
also implies active site is in the ‘external’ chains
(B,D and F)
Antibodies - CDRs
The antibody active site is always in the CDRs,
which are in the variable part of the antibody
• CDRs H3 and L3 are
most likely to be in the
active site.
• At least 4 CDRs in the
active site
CDRs location utility
• The light and heavy chain has conserved areas
which enables us to align a given sequence to a
consensus sequence which was built using
statistical data.
• This alignment is then used to locate the CDRS
area.
• This information may be used in docking
programs, in the docking process itself (budda) or
in a filtering process (kely).
Antibodies Tyr, Trp and Arg
propensities
• Antibodies active sites have a high propensities of
Tyr,Trp and Arg.
• This property may be used to filter out docking
results or even be used in the scoring function. (we
used both)
Symmetry
• Both antigens (and also the capri1 enzyme) have
a rotational symmetry.
• ‘rmsd-like distance function’ Clusterring is used to
gather transformations which are symmetrically
similar.
Clustering different alg results
• Any algorithms performs well on some
targets and less on other.
• Since 10 results should have been submitted
to each target it seemed reasonable to gather
results from different algorithms, re-score
them, and then re-cluster them.
CAPRI Docking Flow
Molecular Surface
representation
Critical points
selection
Matching of
critical points
Clustering and
Scoring
• Compute Connolly and Shuo surface
representation.
• Compute CDRs in case of AntibodyAntigen docking.
• Select knobs and holes for CDRs only
• Match critical points - use 2 points
and their normals for faster matching.
• Cluster transforms.
• Compute geometric score.
• Apply CDRs, Tyr-Trp, NS, interface
connectivity, symmetry filters.
Enzyme – inhibitor test set
results (unbound)
Description
Alpha-chymotrypsinogen / Pancreatic secretory trypsin inhibitor
Alpha-chymotrypsin / Ovomucoid 3rd Domain
Beta-trypsin / Pancreatic trypsin inhibitor
Trypsinogen / Pancreatic secretory trypsin inhibitor
Subtilisin Novo / Chymotrypsin inhibitor 2
Subtilisin BPN / Subtilisin inhibitor
Subtilisin Carlsberg / Eglin C
Kallikrein A / Trypsin inhibitor
Trypsin / APPI
Trypsin / CMT-1
Trypsin / BBI
Alpha-chymotrypsin / Eglin C
Barnase / Barstar
Mouse Acetylcholinesterase / inhibitor
Human Uracil-DNA glycosylase / inhibitor
Virus Uracil-DNA glycosylase / inhibitor
Papain / Stefin B
Thermitase / Eglin C
Alpha-Thrombin / Hirudin
Ribonuclease inhibitor / Ribonuclease A
Acetylcholinesterase / Fasciculin II
Trypsin / Sotbean Trypsin inhibitor
Ligand
1HPT
2OVO
6PTI
1HPT
2CI2
3SSI
1ACB(I)
6PTI
1AAP
1PPE
1TAB
1CSE(I)
1A19
1FSC
1UGI
1UDI
1STF
2TEC
4HTC
7RSA
1FSC
1BA7
Receptor Complex BestRMSD Rank
1CHG
1CGI
1.28
1
5CHA
1CHO
1.22
1
2PTN
2PTC
2.83
35
2PTN
1TGS
1.69
1
1SUP
2SNI
2.07
11
1SUP
2SIC
1.59
6
1SCD
1CSE
1.65
10
2PKA
2KAI
2.37
111
1BRA
1BRC
1.73
292
2PTN
1PPE*
2PTN
1TAB*
5CHA
1ACB
0.783
2
1A2P
1BRS
1.57
2
1MAA
1MAH
1.4
14
1AKZ
1UGH
1.55
1
1UDH
1UDI*
1PPN
1STF*
1THM
2TEC*
2HNT
4HTC*
2BNH
1DFJ
2.05
3
2ACE
1FSS
2.27
1
2PTN
1AVW
1.95
6
Antibody-Antigen test set results
(unbound/bound)
Description
IgG1 D44.1 Fab fragment / Lysozyme
IgG1 Fab fragment / Lysozyme
IgG1 E8 Fab fragment / Cytochrome C
Antibody Fab 5G9 / Tissue factor
Jel42 Fab Fragment / A06 Phosphotransferase
Hyhel - 5 Fab / Lysozyme
Hyhel - 63 Fab / Lysozyme
IgG1 Fv Fragment / Lysozyme
Antibody Hulys11 Fv / Lysozyme
Fab NC41 / Neuraminidase
Fab NC10 / Neuraminidase
Vh Single-Domain Antibody / Lysozyme
Igg1-lamda Fab / Hemagglutinin
Bh151 Fab / Hemagglutinin
Igg1-k Fab / Hemagglutinin
IgG1 Fab fragment / Lysozyme
Fv Fragment / Lysozyme
Igg1 Fab Fragment (Hyhel-5) / Lysozyme
Ligand
1LZA
1HHL
1HRC
1BOY
1POH
1DKJ
3LZT
1GHL
3LZT
7NN9
7NN9
1LZA
2VIU
Receptor
1MLB
1FBI
1QBL
1FGN
2JEL
1BQL
1DQQ
1JHL
1BVL
1NCA
1NMB
1MEL
2VIR
Complex
1MLC
1FBI*
1WEJ
1AHW
2JEL*
1BQL*
1DQJ
1JHL*
1BVK
1NCA*
1NMB*
1MEL*
2VIR*
2VIU
2VIU
1EO8
1QFU
1EO8*
1QFU*
1LZA
1LZA
5LYM
1FDL
1VFB
3HFL
1FDL
1VFB
3HFL
Best RMSDRank
1.26
1
1.3
1
1.12
11
1.37
1
1.27
2
1.14
1
2.38
258
0.87
4
1.12
3
0.949
1
1.09
34
1.7
1.26
1.45
1.18
1.12
191
79
8
2
2
New classes and utilities
MoleculeGrid class - new class in GAMB++ library.
The class can compute molecule grid with distance
function, volume function and normals for critical
points.
CDR utility - utility that finds CDRs for antibody, by
aligning new sequence to consensus sequence.
Symmetry and Clustering utility
New docking version of budda - including new grid
representation, two points and normals matching.