CONFOLD: Residue-Residue Contact-guided ab initio Protein Folding

Badri AdhikariStudent of Dr. Jianlin Cheng

Department of Computer ScienceUniversity of MissouriColumbia MO 65211

3/13/2015

The 12th Annual MCBIOS Conference,Little Rock Marriott Conference and Convention

CenterLittle Rock, AR

predict contacts

Introduction

contacts

Machine-learning based

DNcon, SVMcon

Coevolution-derivedPSICOV, CCMpred, DCAfold

HybridMetaPSICOV

ab initioEVFOLD

fragment-basedFRAGFOLD, ROSETTA

improvement

protein.rnet.missouri.edu/confold/

build 3D models

CONFOLD

MetaPSICOVDr. David Jones at University College London (UCL)

mfDCADr. José Onuchic at UC San Diegohttp://dca.rice.edu/portal/dca

GREMLINDr. David Baker at University of Washington

CCMpredDr. Johannes Söding at University of Munich (LMU Munich)

FreeContactDr. Burkhard Rost at Technische Universität München (TUM)

DNconDr. Jianlin Cheng at University of Missouri Columbia

EVFOLDDr. Chris Sander at Memorial Sloan Kettering Cancer Center

EVFOLDDr. Debora MarksHarvard Medical School

predict contacts

Introduction

contacts

Machine-learning based

DNcon, SVMcon

Coevolution-derivedPSICOV, CCMpred, DCAfold

HybridMetaPSICOV

ab initioEVFOLD

fragment-basedFRAGFOLD, ROSETTA

improvement

protein.rnet.missouri.edu/confold/

build 3D models

CONFOLD

residue-residue contacts in proteins

a contact in a proteinResidues i and j are in contact if

distance(Cβi, Cβj) ≤ 8 Å

Variations:- use of Cα instead of Cβ- other thresholds like 7 Å or 12 Å- minimum sequence separation of

5 or 6 residues

# of contacts and threshold

at 8 Å threshold at 12 Å threshold at 20 Å threshold

building 3D models using predicted contacts

EVFOLD vs FRAGFOLD

to use, or not to use fragments,- that is the question.

http://en.wikipedia.org

1. Reconstruct secondary structuresreconstruct Helices and beta-sheets

2. Handle noise in predicted contactsIf we try to satisfy all contacts,the model can easily jumble up

ab initio - Challenges

CONFOLD method- convert secondary structures in to distance,

angle and h-bond restraints- combine contact restraints and secondary

structure restraints using weighting schemes- use of customized CNS suite v1.3 for modelling- two stage model-building method

- improves beta-sheet quality- improves accuracy of models

build 3D

models

translate using derived restraints

restraints - dihedral - distance - h-bonds

restraints - distance

secondary

structure

contacts

select all or top-xL contacts

build 3D

models

restraints (updated) - dihedral - distance - h-bonds

restraints (filtered) - distance

weights

detect β-sheets

filter unsatisfied contacts

Results

Reconstructing Secondary Structures

Helix residues- 77 out of 79 on averageStrand residues- 33 out of 42 on average

Data Set:24 proteins in Tc category of CASP11

1YPI 2QOM

Evaluation of best models

SPTB2_HUMAN

RMSD calculations

Evaluation of all models

How does the two-stage idea work?

stage 1 stage 2TM-score = 0.5 TM-score = 0.61

Conclusion• We can reconstruct secondary structures, helices

and beta-sheets, in proteins from scratch, very well

• Existing ab inito methods for building 3D models using contacts can be improved

• Two-stage model building approach can improve models’ accuracy by removing noisy contacts

Acknowledgementsto my advisor Dr. Cheng and

to my friends Deb, Renzhi, Jilong and Jie in our research lab.