Overview of First CAPRIBlind Protein Docking Experiment

Dave Ritchie

Department of Computing ScienceKing’s College, University of Aberdeen

Aberdeen AB24 3UE, UK.

Overview of First CAPRIBlind Protein Docking Experiment

Contents

• CAPRI Background

• Hex Docking Algorithm

• CAPRI Target Structures

• CAPRI Participants & Algorithms

• CAPRI Results

• Conclusions, Future Directions

CAPRI“Critical Assessment of Predicted

Interactions”

• CASP did have a Docking Section

• Docking was a side-show ?

• Too few targets, too easy/hard ?

• Hence CAPRI

Janin, Wodak, Sternberg, Moult,Ten Eyck, Vajda, Henrick

• To assess the state of the art

• To promote developments in the field

• Hosted by EBI (Henrick, Tate)

• 2001/2: 7 targets made available

• ∼ 20 International groups participated...

Lactobacillus HPrK / Hpr (CAPRI Target 1)

Hex: Protein Shape Complementarityusing Density Representations

τσ(r)

(r)

Surface Density: σ(r) =

{

1; r ∈ surface skin volume

0; otherwise

Interior Density: τ (r) =

{

1; r ∈ VDW volume

0; otherwise

Favourable:

∫

(σA(rA)τB(rB) + τA(rA)σB(rB))dV

Unfavourable:

∫

τA(rA)τB(rB)dV

Penalty Factor: Q = 11

Score: SAB =

∫

(σAτB + τAσB − QτAτB)dV

Spherical Polar Shape Reconstruction

(Looking at MCV Antibody CDR Loops)

τ (r) =N

∑

nlm

aτnlmRnl(r)ylm(θ, φ)

Image Expansion Coefficients

A Atom Gaussians -

B N = 16 1,496

C N = 25 5,525

D N = 30 9,455

Correlations - Overlap as a Function ofCoordinate Operations

Basic Overlap:

∫

σA(r)τB(r)dV =

N∑

nlm

aσnlmbτ

nlm

Rotation: R(α, β, γ)σA(r) =N

∑

nlm

aσ′nlmRnl(r)ylm(θ, φ)

Translation: T (R)σA(r) =N

∑

nlm

aσ′′nlmRnl(r)ylm(θ, φ)

Rotated Coeffs: aσ′nlm =

l∑

m′=−l

R(l)mm′(α, β, γ)aσ

nlm′

Translated Coeffs: aσ′′nlm =

N∑

n′l′

T(|m|)nl,n′l′(R)aσ

n′l′m

Hence:

∫

σ′A(r)τ ′′

B(r)dV =N

∑

nlm

aσ′nlmbτ ′′

nlm etc.

Search: Calculate for ∼ 109 orientations

P3 1.8GHz Xeon: ∼ 106/s @ N = 16; ∼ 105/s @ N = 30

Summary of Hex Docking Strategy

• Contour VDW & SAS surfaces – “marching tetragons”

• Sample surface volumes onto (0.6A)3 grid

• Calculate shape & electrostatic coefficients – once

• Scan search space with N=16 correlations (shape only)

• (Optionally constrain search to one or both epitopes)

• Re-score top 10,000 with N=30 (+electrostatics)

• Refine top 500 by soft OPLS minimisation

• Cluster solutions

• Output best member of each cluster

• Pray!

Docking Very Large Molecules

The 7 CAPRI Docking Targets

Target Receptor Ligand Type Complex Lab

1 HPr Kinase HPr U/U Fieulaine et al. Janin

2 Rotavirus VP6 MCV U/B Vaney et al. Rey

3 Hemagglutinin HC63 U/B Barbey-Martin et al. Knossow

4 α -Amylase AMD10 U/B Desmyter et al. Cambillau

5 α -Amylase AMB7 U/B Desmyter et al. Cambillau

6 α -Amylase AMD9 U/B Desmyter et al. Cambillau

7 SpeA TCR 14.3.D U/U Sundberg et al. Mariuzza

• At least one docking partner presented in its unbound form

• Participants permitted 5 attempts for each target

• Any predictive approach allowed: homology/literature, etc.

Participants & Algorithms (Selected)

Predictor Affiliation Software Algorithm

Abagyan Scripps ICM Force Field

Camacho/Vajda Boston CHARMM Force Field Refinement

Gardiner Sheffield GAPDOCK Shape + Area GA

Sternberg/Smith Imperial FTDOCK FFT

Bates/Fitzjohn ICRF Guided Docking Force Field

Ten Eyck/Mitchell SDSC DOT FFT

Vakser/Tovchigrechko SUNY/MUSC GRAMM FFT

Olson Scripps Harmony Spherical Harmonics ?

Weng/Chen Boston ZDOCK FFT

Eisenstein Weizmann MolFit FFT

Wolfson/Nussinov ? BUDDA/PPD Geometric Hashing

Iwadate Kitasato TSCF Force Field + Solvent

Ritchie/Mustard Aberdeen Hex Spherical Polar Fourier

Palma Lisbon BIGGER Geometric + Electrostatic

Gray/Baker Washington ? Monte Carlo + FlexibilitySeveral other participants (not shown) attempted a small no. of targets

CAPRI Results (Unofficial)

Predictor Software Algorithm T1 T2 T3 T4 T5 T6 T7

Abagyan ICM FF + + +

Camacho CHARMM FF + +

Gardiner GAPDOCK GA +

Sternberg FTDOCK FFT +

Bates Guided Docking FF +

Ten Eyck DOT FFT +

Vakser GRAMM FFT

Olson Harmony ?

Weng ZDOCK FFT + + +

Eisenstein MolFit FFT + + +

Wolfson BUDDA/PPD GH +

Iwadate TSCF FF

Ritchie Hex SPF + +

Palma BIGGER GF +

Gray ? MC + +

NB. Some predictions were disallowed: “slamming” or > limit of 5 entries

Hex 3.1 Results for CAPRI Targets 1–7

Target Description Constraints Samples Rank Contacts RMS Time/h

1 HPrK/HPr β1 ≤ 45◦ 1.5 × 108 −/1 2/56 − 0.2

2 VP6/MCV β1, β2 ≤ 45◦ 5.6 × 108 −/5 0/52 − 5.3

3 HA/HC63 β1, β2 ≤ 45◦ 6.3 × 108 4/5 43/63 7.43 6.5

4 Amylase/AMD10 β1, β2 ≤ 45◦ 5.6 × 108 −/5 0/58 − 4.7

5 Amylase/AMB7 β1, β2 ≤ 45◦ 5.6 × 108 −/5 0/64 − 4.7

6 Amylase/AMD9 β1, β2 ≤ 45◦ 5.6 × 108 5/5 53/65 2.16 4.7

7 SpeA/14.3.D β1 ≤ 45◦ 1.5 × 108 −/5 2/37 − 0.25

Submitted Orientation for Target 1

Docked Orientation for Target 3

Docked Orientation for Target 6

Target 7 – What Went Wrong?

CAPRI Targets 1–7 Revisited

Shape Only +EL +MM +EL+MMTarget R/L RMS N Rank RMS Rank RMS Rank RMS Rank RMS

1 2.39/0.57 30 1 4.06 11 4.06 33 4.18 19 4.18

2 0.62/0 30 37 3.05 41 3.05 123 2.90 119 2.90

3-AC 1.13/0 30 112 9.99 18 2.75 3 6.95 3 6.95

3-CE 1.13/0 30 62 8.91 39 8.91 18 8.43 15 8.43

4 0.41/0 30 63 3.05 10 3.05 125 8.74 106 8.74

5 0.41/0 30 826 2.74 118 2.74 18 2.49 20 2.49

6 0.41/0 30 1 0.75 1 0.75 1 0.64 1 0.64

7 1.09/0.49 30 122 5.37 295 9.22 39 5.60 18 8.83

Average Rank: 175 76 51 43

Log-Average: 55 38 29 23

Conclusions & Future Directions

Hex

• Fast and reasonably accurate: 2 out of 7 ain’t bad !

• SH surface sampling works well for large molecules

• Electrostatics & Soft OPLS minimisation (usually) help

• Clustering certainly helps

• Need better model of flexibility than “soft docking”...

• Eigenvector analysis of Essential Dynamics ??

CAPRI

• Protein Docking Algorithms are Improving

• Special Issue of PSFG, 1st Quarter 2003

• Annual Meetings: Alternating Theoretical/Assessment

• Ongoing Call to Crystallographers for Targets...

Acknowledgements

DWR: BBSRC 1996 – 2000

Thanks To:

Russell HamiltonGuillaume Valadon

CAPRI Organisers & The EBI

Hex Software & Preprints

http://www.biochem.abdn.ac.uk/hex/

CAPRI Call For Targets

http://capri.ebi.ac.uk/call for targets.html