what determines the structure of the native folds of proteins?
DESCRIPTION
What determines the structure of the native folds of proteins?. Antonio Trovato INFM Università di Padova. Outline. Protein folding problem: native sequences vs. structures - sequences are many and selected by evolution - folds are few and conserved - PowerPoint PPT PresentationTRANSCRIPT
What determines the structure of the native folds of proteins?
Antonio Trovato
INFMUniversità di Padova
Outline
• Protein folding problem: native sequences vs. structures
- sequences are many and selected by evolution - folds are few and conserved
• Simple physical model capturing of main folding driving forces: hydrophobicity, sterics, hydrogen bonds
• Protein energy landscape is presculpted by the general
physical-chemical properties of the polypeptide backbone
Protein Folding Problem
• Central Dogma of Molecular Biology: DNA RNA Amino Acid Sequence (primary structure) Native conformation (tertiary structure) Biological Function• Anfinsen experiment: small globular proteins fold reversibly
in vitro to a unique native state free energy minimum• Which Hamiltonian?• Which structure?• Levinthal paradox: how does a protein always find its native state in ms-s time?
Energy landscape paradygm (from cubic lattice models)
• Levinthal paradox: how to reconcile the uniqueness of
the native state with its kinetic accessibility?
• Principle of minimal frustration Energy-entropy relationship is carving a funnel for designed sequences in the energy landscape
Conformations
Ener
gy
Ener
gy
Conformations
However Only a Limited Number of Fold Topology Exists
Protein sequences have undergone evolution but folds have not…. they seem immutable
- M. Denton &C. Marshall, Nature 410, 417 (2001).
- C. Chotia & A.V. Finkelstein, Annu. Rev. Biochem. 59, 1007 (1990).
- C. Chotia, Nature 357, 543 (1992).
- C. P. Pointing & R.R. Russel, Annu. Rev. Biophys. Biomol. Struct. 31, 45 (2002).
- A.V. Finkelstein, A.M. Gutun & A.Y. Badretdinov, FEBS Lett. 325, 23 (1993).
Most commonsuperfolds
the same fold can housemany different sequencesand perform severalbiological functions
can the emergence of a rich yet limited number of foldsbe explained by means of simple physical arguments?
Compactness-Hydrophobicity
HH PP
SolventSolvent
Secondary structures
Linus Pauling:
L. Pauling & R.B. Corey, Conformations of polypeptides chains with favored orientations around single bonds: two new plated sheets, PNAS 37, 729-740 (1951); ibid with H.R. Branson 205-211.
motifs. and with consistent is bondHydrogen
Steric constraints
D e g r e e s o f f r e e d o m
i i
i
i - t h
A l l b o n d l e n g t h a n d b o n d a n g l e s a r e k e p t f i x e de x c e p t t h a t N C C ’ b o n d a n g l e i s a l l o w e d t o p e r t u b e d s l i g h t l y .T o r s i o n a l a n g l e a b o u t t h e p e p t i d e b o n d o5180
Ramachandran plot: Only certain regions in the phi-psi plane are allowed for most of the a.a.; constraints are specific G.N. Ramachandran & Sasisekharan, Conformations of polypeptides and proteins, Adv. Protein. Chem. 23, 283-438 (1968).
Strong Hint
encourage secondary structure
Both hydrogen bonding and steric interaction
Thick HomopolymersFeatures & Motivations
• Chain directionality breaks rotational symmetry of the tethered objects.• Need for a three body interaction.• Continuum limit without singular interaction potentials 2-body interaction must be discarded.• Nearby objects due to chain constraint do not necessarily interact.• Compact phase of relatively short thick polymers are different from the
compact phase of the standard string and beads model.
O. Gonzalez & J.H. Maddocks, PNAS 96, 4769 (1999).J.R. Banavar, O. Gonzalez, J.H. Maddocks & A. Maritan, J. Stat. Phys.110,35(2003).A. Maritan, C.Micheletti, A. Trovato & J.R. Banavar, Nature 406, 287 (2000) .J.R. Banavar, A. Maritan, C. Micheletti & A. Trovato, Proteins. 47, 315 (2002).J.R. Banavar, A. Flammini, D. Marenduzzo, A. Maritan & A. Trovato, ComPlexUs 1, 8 (2003).
Optimal packing of short tubes leads to the emergence of secondary structures
Optimal helix (pitch/radius=2.512..):generalization of Kepler problemfor hard spheres
Nearly parallel placement ofdifferent nearby portions ofthe tube
Formulation of the Model
tionRepresenta C
• Tube Constraint (three-body constraint)
• Hydrogen bonding geometric constraint
• Hydrophobic interaction: eW
• Local bending penalty: eR
Formulation of the Model: Rules. H-Bond
From 600 proteins in the PDB
tionRepresenta C
i
i+1
j+1
j
j-1
ib
jb
binormals at the j-th and i-th residues1
jj bb ij
rb jiji rb
rij
How Many Parameters?
Hydrogen bonding
Local i – i+3 eH = -1
Non-Local i – i+5, i+6,… eH = -0.7
Cooperativity ecoop = -0.3
Remark: no H-bond between i – i+4 !
-5 -4 -3 -2 -1 0 +1 +2 +3 +4
eW
4
3
2
1
0
eR
Ground State Phase Diagram
ew = water mediated hydrophobic interaction
No sequence specificity: HOMOPOLYMER
eR = bending penalty
Structureless Compact Swollen
?
Ground State Phase Diagram
-5 -4 -3 -2 -1 0 +1 +2 +3 +4
eW
4
3
2
1
0
eR
SwollenStructureless Compact
bend
ing
ener
gy
attraction energy
Ground State Phase Diagram
All Minima In The Vicinity Of the Swollen Phase (Marginally Compact)
Similar structures for longer chains(48 residues)
Pre-sculpted energy landscape
Sequence selection is easy!
Free Energy Landscape At Non Zero Tle
ngth
= 2
4
Extended conformationis entropically favored:
implication for aggregationin amyloid fibrils?
Aggregation of short peptides
Aggregation in amyloid fibrils is a universalfeature of the polypeptide backbone chain
Jimenez et al., EMBO J. 18, 815-821 (1999)
Conclusions
• Simple physical model capturing geometry and symmetry of main folding driving forces: hydrophobicity, sterics, hydrogen bonds
• Proteinlike conformations emerge as coexisting energy minima for an isolated homopolymer in a marginally compact phase flexibility ; aggregation in amyloid fibrils is promoted increasing chain concentration
• The energy landscape is presculpted by the physical-chemical
properties of the polypeptide backbone; - design for folding is “easy”: neutral evolution - evolutionary pressure for optimizing protein-protein
interaction (active sites, binding sites) and against aggregation
Acknowledgments
Jayanth R. Banavar (Penn State)Alessandro Flammini (SISSA Trieste)Trinh Xuan Hoang (Hanoi)Davide Marenduzzo (Oxford)Amos Maritan (INFM Padova)Cristian Micheletti (SISSA Trieste)Flavio Seno (INFM Padova)