Tweaking structures: working on the fiddly bits Kevin Karplus - - PowerPoint PPT Presentation

Tweaking structures: working on the fiddly bits

Kevin Karplus

karplus@soe.ucsc.edu

Biomolecular Engineering Department University of California, Santa Cruz

Tweaking structures – p.1/12

Outline of Talk

Cost functions Clash detection Sidechain quality H bond quality Predicted backbone structure Conformation change operators JiggleSegment JiggleSubtree TweakHbond TweakPsiSegment TweakPsiSubtree TweakPhiSegment TweakPhiSubtree TweakPeptide TweakPsiPhiSegment TweakPsiPhiSubtree BackRub BigBackRub

Tweaking structures – p.2/12

Clash Detection

Simple clash detector with minimum legal distance for each pair of atoms (no attractive term). Distances trained (badly) on large set of high-quality structures.

0.2 0.4 0.6 0.8 1 0.2 0.4 0.6 0.8 1 cost dist/min_dist Soft clash cost: ratio<1? 1-ratio**6 : 0

Tweaking structures – p.3/12

Sidechain quality

9-dimensional space (where are CA-1, CA+1, and distal point on sidechain) Gaussian mixture for “rotamer library” Estimates joint probability of backbone and rotamer, not rotamer conditioned on backbone. Redoing our sidechains with SCWRL gives about equal number of better and worse models.

Tweaking structures – p.4/12

Our sidechains are not supremely good

• 0.15
• 0.1
• 0.05

0.05 0.1 0.15 1 10 100 SAM-T08-server - SAM-T08-server-scwrl (all-atom rmsd) SAM-T08-server-scwrl (all-atom rmsd) All whole chains SAM-T08-server-scwrl better SAM-T08-server better

Tweaking structures – p.5/12

Hbonds

Different cost functions for different types of H-bonds. separation=3 separation=4

• ther separation

4 non-backbone classes Backbone H-bonds most carefully done: distance non-planarity asymmetry donor-acceptor-carbon angle

Tweaking structures – p.6/12

Predicted backbone structure

Local structure prediction using neural nets Several alphabets: Bystroff’s φ-ψ classification de Brevern’s protein blocks CA-CA-CA-CA α torsion angle Cost function uses

log P(class|neural net) P(class|amino acid)

Tweaking structures – p.7/12

Jiggle, TweakHbond

JiggleSegment JiggleSubtree: make a small rigid

• transform. Move either

the segment (between chain breaks) a subtree consisting of several segments. TweakHbondSegment or TweakHbondSubtree same idea, but donor or acceptor has very small change to position.

• ther atoms of segment or subtree may move further

Tweaking structures – p.8/12

TweakPhi, TweakPsi, TweakPeptide

TweakPhiSegment, TweakPhiSubtree, TweakPsiSegment, TweakPhiSegment: Make small change to angle. TweakPsi generally more productive than TweakPhi. TweakPeptide: rotates peptide plane about axis through two CA atoms.

Tweaking structures – p.9/12

TweakPsiPhi Segment/Subtree

Make small change to psi angle and opposite change to next phi angle. Note: axes of rotations almost parallel on opposite ends

• f peptide plane.

Moves rest of segment (or subtree) along circular arc without reorienting it much.

Tweaking structures – p.10/12

BackRub, BigBackRub

Rotate chain segment about line between two CA atoms. For Backrub, CA are 2 apart on backbone. Reposition first and last peptide planes to try to get

• ptimal superposition on new CA positions but old N

and O positions (to preserve Hbonds). These tweaks tend to have high success rate and so can be done with larger angular changes than other tweaks.

Tweaking structures – p.11/12

Web sites

CASP8 working files: http://www.soe.ucsc.edu/˜karplus/casp8/ List of my papers:

http://www.soe.ucsc.edu/˜karplus/papers/paper-list.html

These slides: http://www.soe.ucsc.edu/˜karplus/papers/

tweak-slides-2008-dec.pdf

UCSC bioinformatics (research and degree programs) info:

http://www.soe.ucsc.edu/research/compbio/

Tweaking structures – p.12/12