Hydrogen bonds in Rosetta: a phenomonological study Jack Snoeyink Dept. of Computer Science UNC Chapel Hill.

Hydrogen bonds in Rosetta:a phenomonological study

Jack SnoeyinkDept. of Computer ScienceUNC Chapel Hill

Key points

My biases Hydrogen bonds in Rosetta

Structure-derived potential of KMB03 Existing definition/scoring Comparing natives & decoys Proposed recategorization

Bad smells in code Open questions

Phenomenology defined:

Movement originated by E. Husserl in 1905

A philosophy based on the premise that reality consists of objects and events as they are perceived or understood in human consciousness and not of anything independent of human consciousness.

Phenomenology defined:

Movement originated by E. Husserl in 1905

A philosophy based on the premise that reality consists of objects and events as they are perceived or understood in human consciousness and not of anything independent of human consciousness.

Structure-derived potential KMB03

Energy from observed structures: distance dependence for helix

0

200

400

600

800

1000

1200

1400

1.45

1.55

1.65

1.75

1.85

1.95

2.05

2.15

2.25

2.35

2.45

2.55

2.65

2.75

2.85

Structure-derived potential KMB03

Energy from observed structures: statistically derived energies…

-2

-1

0

1

2

3

1.45

1.55

1.65

1.75

1.85

1.95

2.05

2.15

2.25

2.35

2.45

2.55

2.65

2.75

2.85

Structure-derived potential KMB03

Energy from observed structures: as implemented in Rosetta…

Three tasks in Hbond scoring

Identify pairs of atoms that Hbond

Classify Hbond types

Evaluate energies for Hbonds

Rosetta++ mixes these tasks together…

Three tasks in Hbond scoring

As described in KMB03 Identify pairs of atoms that Hbond

Params: AH distance, , Classify Hbond types

BB: helix, strand, other; AH distance SS,BS,SB: acceptor hybridization; AH dist

Evaluate energies for Hbonds Sum three potentials on AH distance, , , Amino acid weights Residue neighbors for donor/acceptor

Three tasks in Hbond scoring

As implemented in Rosetta++ Identify pairs of atoms that Hbond

Params: AH distance, , Classify Hbond types

BB: separation short |sep|≤4; long range SS,BS,SB: acceptor hybridization; AH dist

Evaluate energies for Hbonds Sum three potentials on AH distance, , Amino acid weights OR

Residue neighbors for donor/acceptor

SS bonds: native & decoy

sp2

ED

QN

bb

sp3

TS

Y

ring

H

dist

SS bonds: native & decoy

sp2

ED

QN

bb

sp3

TS

Y

ring

H

dist Natives: Dunbrack set of 3157 structures

some pdb errors Decoys: Best 20 for each of Rhiju’s ab

initio runs on 62 structures small proteins few parallel beta strands

Rosetta places Hs & determines Hbonds Filter energies < -0.1 Visualization: Tufte’s small multiples Normalization

Express counts as fraction of all Hbonds to support comparison of colors in each plot

Plot with common x axis; scale y to max height

Energy distribution of bonds involving a sidechain atom before/after filtering

Number (and percentage) of bonds under the existing classification

Counts Percentage

Native Decoys Native Decoys

BB

Helix (+/-4) 185,204 38,128 32.28 50.66

Turn (+/-3) 79,110 8,983 13.79 11.94

Other 150,945 19,459 26.31 25.85

S

sp2 ED QB bb 132,522 6,448 23.10 8.57

sp3 TS Y 23,641 2,062 4.12 2.74

ring H 2,325 184 0.41 0.24

TOTALS 573,747 75,264 100.00 100.00

Observations

Rosetta does well at optimizing what it is told.

Decoy distributions are more sharply peaked than natives.

Relax preserves more non-helix bonds than ab initio, but produces same shapes for param distrib’ns. To test changes, it suffices to run relax.

SS bonds: native & decoy

sp2

ED

QN

bb

sp3

TS

Y

ring

H

dist

SS bonds: native & decoy

sp2

ED

QN

bb

sp3

TS

Y

ring

H

dist

SS,BS,SB bonds: native & decoy

sp2

ED

QN

bb

sp3

TS

Y

ring

H

dist

AH Distance

NB: donor effectssmall #

omit Cbimodal HR & QNacc

Theta A-H-D angle

NB: small #s

widthR NE&NH

PsiAHD angle

NB: RE & EDacc

Chi A2-A torsion

NB: Polar &chargedprefs

__ H-D torsion

NB: Polar &chargedprefs

Three tasks in Hbond scoring

Proposed changes Identify pairs of atoms that Hbond

Params: AH distance, , Classify Hbond types

BB: finer separation (Beta?) SS,BS,SB: finer don/acc chemical types

Evaluate energies for Hbonds: options1. Sum three potentials on AH distance, , 2. Potential on three variables AH distance, , 3. Add neighbors4. Add a torsion as 4th or 5th variable Weights for tuning different terms

Backbone bonds

AH distance

Backbone bonds

theta

Parallel vs Anti-parallel beta

The standard figures are misleading;

parallel and anti-parallel form similar distance, , distributions.

Backbone bonds

psi

Backbone bonds

chi torsion

Backbone bonds

AH-DD2 torsion

Refactoring Hbonds

Recategorizing should eliminate long-range & short-range Hbonds;which are used outside of hbonds.cc – they shouldn’t need to be.

Duplicated code in minimizers needs to be brought back into hbonds.cc

Refactoring

In code, a function should do one thing well.

When a function you work with is doing too many things, split it.

Duplicating code indicates that something is designed wrong.

Avoid magic numbers.