beyond linus pauling: conformation dependence of ideal geometry in proteins

Beyond Linus Pauling: Conformation dependence

of ideal geometry in proteins

Donald S. BerkholzP. Andrew Karplus lab

What is ideal geometry?

α α

R

R

NH2

Where do you encounter ideal geometry?

Where do you encounter ideal geometry?

Where do you encounter ideal geometry?

Where do you encounter ideal geometry?

Where do you encounter ideal geometry?

Ideal geometry paradigm is limited

N-Cα-C

A new paradigm

N-Cα-C

Why is this important?

RMSD(N-Cα-C)

Engh & Huber = 2.54°Conformation-Dependent Library = 1.65°

Why is this important?

Our approach

Our approach

Protein Geometry Database

Our approach

Protein Geometry Database

≤1.0 Å resolution

Our approach

Protein Geometry Database

≤1.0 Å resolution Residues in PGD

19,516 (≤90% ID) 16,975 (≤25% ID)

Our approach

Protein Geometry Database

≤1.0 Å resolution Residues in PGD

19,516 (≤90% ID) 16,975 (≤25% ID)

Conformation-Dependent Library

What trends exist?N-Cα-Caverage

φ

ψ

107.5 114.0

Averages known with high certaintyN-Cα-C

standarderror

ψ

φ0.1 1.1

Dependent on local torsion angle

α α

R

R

NH2

Dependent on local torsion angle

C-1-N-Cα

average

φ

ψ

α α

R

R

119.5 126.0

NH2

Dependent on local torsion angle

N-Cα-Caverage

C-1-N-Cα

average

φ

ψ

φ

ψ

α α

R

R

119.5 126.0 107.5 114.0

NH2

Dependent on local torsion angle

N-Cα-Caverage

C-1-N-Cα

averageCα-C-N

+1

average

φ

ψ

φ

ψ

φ

ψ

α α

R

R

119.5 126.0 107.5 114.0 114.5 119.5

NH2

Rationalizing φ = 40-90°

Rationalizing φ = 40-90°

C-1-N-Cα

average

ψ

ω-1

average

ψ

O-1-C

-1-N

average

ψ

φφ

N-Cα-Cβaverage

ψ

φφ

φ

109.0 114.0119.5 126.0121.8 123.4

172.0 189.0

Rationalizing φ = 40-90°

C-1-N-Cα

average

ψ

ω-1

average

ψ

O-1-C

-1-N

average

ψ

φφ

N-Cα-Cβaverage

ψ

φφ

φ

109.0 114.0119.5 126.0121.8 123.4

172.0 189.0

New paradigm for peptide planarity

PDB: 2cws at 7.0σ

New paradigm for peptide planarity

ω average

ω-1

average

φ

φ

ψ

ψ

PDB: 2cws at 7.0σ 172.0 186.0

172.0 189.0

How could CDL improve refinement?

How does CDL improve refinement?

How does CDL improve refinement?

RMSD(N-Cα-C)

Resolution 2.5 Å 1.7 Å

Engh & Huber 3.23° 3.56°Conformation-Dependent Library

1.32° 1.54°

Conclusion

N-Cα-Caverage

φ

ψ

The old paradigm

110.5 110.5

Conclusion

N-Cα-Caverage

ψ

φ

N-Cα-Caverage

φ

ψ

The old paradigm The new paradigm

107.5 114.0110.5 110.5

Why is this important?

RMSD(N-Cα-C)

Engh & Huber = 2.39°Conformation-Dependent Library = 1.50°

Why is this important?

What is the impact of these variations?

Approach to trend analysisN-Cα-Caverage

ψ

φ

Approach to trend analysisN-Cα-Caverage

ψ

φ

Peptide planarity is overexaggerated

Kang 2004