Post on 21-Jan-2016
description
Exploring the Universe of Protein Structures beyond the
Protein Data Bank
Flavio Seno
Dipartimento di Fisica e Astronomia
Universita’ di Padova
Means, Methods and Results in the Statistical Mechanics of Polymeric Systems.
Toronto 21-22 June 2012
What are their distinctive properties?secondary structures
stabilized by hydrogen bonds
Folds:arrangements of secondary structures in the space
There is a limited set of folds:same folds used to perform different
functions
There is not macroscopic evolution:multiple separate discoveries during the
course of evolution
Protein structures
Platonic folds : intrinsic features of the order of nature (Denton and Marshall ,Nature 2002)
~ 7000 structures (new sequences) determined every year
Are protein folds determined only by physical and geometrical laws ( crystal structures) and not by the chemistry of the amino-acid sequence?
Is it possible to reproduce them in terms of general principles? Maybe through an homopolymer that captures the main common features of all the aminoacids?
Are the observed folds in a one to one correspondence with the whole possible fold universe?
If not, why? Is there a selection principle?
“SIMILARITY OF PROTEIN STRUCTURES IMPOSED BY
SOME PHYSICAL REGULARITIES” (Finkelstein-Ptitsyn 2002)
Minimal Coarse-Grained ModelT.X. Hoang, L. Marsella, A. Trovato, J.R. Banavar, A. Maritan, F.S. PNAS, vol 103, 6883 (2006)
tionRepresenta C
• Excluded volume (self-avoiding tube)
• Hydrogen bonding geometric constraint
• Hydrophobic interaction
• Local bending penalty
Ground State Phase DiagramHomopolypeptide structures in the‘marginally compact’ phase
(compact + h-bonds) are protein-like
THE METHOD IS BASED ON AN ARTIFICIAL DYNAMICS (METADYNAMICS)
1) IDENTIFY COLLECTIVE VARIABLES S WHICH ARE ASSUMED TO PROVIDE A RELEVANT COARSE GRAINED DESCRIPTION OF THE SYSTEM
2) TO BIAS THE DYNAMICS ALONG THESE VARIABLES.
METADYNAMICS A Laio, M Parrinello, Escaping free-energy minimaPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF, 99, 12562 (2002)
S
HOW TO FIND STABLE MINIMA WHICH ARE SEPARATED BY BARRIERS THAT CANNOT CLEARED IN THE AVAILABLE SIMULATION TIME
3) RUN IN PARALLEL SEVERAL MOLECULAR DYNAMICS EACH BIASED WITH A METADYNAMIC POTENTIAL
4) SWAPS OF THE CONFIGURATIONS
ATOMISTIC MODEL
• Why VAL? (is small but not too much)
• MD simulations with AMBER force field and package GROMACS
• Bias-exchange METADYNAMICS with 6 replicas
• Six collective variables linked to secondary structure elements
60 AMINO ACIDS POLYVALINE (VAL60)
50 microseconds molecular dynamics simulation
We generate an ensemble of 30000 all-atom conformations SIGNIFICANT SECONDARY STRUCTURE CONTENT AND SMALL RADIUS OF GYRATION
We verify they are local minima also for ALA-60
Structural quality resembles that of real protein
H-BOND ENERGY COMPUTED WITH PROCHECK
RAMACHANDRAN PLOT
QUALITY MEASURE G-FACTOR
FRAGMENT DISTANCE < 0.6 A
0.7 A
FIRST RESULT
FINDING BY MOLECULAR DYNAMICS AT AN ALL-ATOM LEVEL A LIBRARY OF 30000
PROTEIN LIKE STRUCTURES
http://datadryad.org/handle/10255/dryad.1922
The Class Architecture Topology and Homologous superfamily protein structure classification (CATH) is one of the main databases providing hierarchical classification of protein domain structures.
RELATION BETWEEN VAL60 AND REAL PROTEINS
300 FOLDS
40 < L<75
SIMILARITY: TM-SCORE (Zhang Scolnick 2005)
ALLIGNMENTS OF SECONDARY STRUCTURES ALLOWING INSERTIONS AND DELETIONS (COVERAGE)
MINIMIZATION OF THE RELATIVE DISTANCE BETWEEN ALIGNED RESIDUES (RMSD)
TM=0.45
1ib8
1g29
1x9b
COMPARISON
VAL60 VS CATH
40 < L < 75
300 FOLDS1uxy
SECOND RESULT
THE COMPUTATIONAL SETUP USED IN THIS WORK ALLOW US TO EXPLORE THE MAJORITY OF
THE FOLDS IN NATURE (AT LEAST FOR THESE LENGTHS)
COMPARISON
POLYVAL VS CATH
NOT ALL VAL60 ARE PRESENT IN CATH!!!!!!!
TM =0.45
VAL60 7000
CATH 300
THIS MIGHT JUST DEPEND ON THE CHOSEN SIMILARITY THRESHOLD
-Real protein strucures were selected under a bias towards low CO
- protein structures are selected to be topologically less entangled
DO STRUCUTRAL DESCRIPTORS DISCRIMINATE BETWEEN CATH AND VAL60?
CONTACT ORDER:Average sequence separation between contacting residues(related to folding rates Plaxco Simons Baker 1998)
THIRD RESULT
THERE IS NO ONE-TO-ONE CORRESPONDENCE BETWEEN PDB LIBRARY AND THE ENSEMBLE OF
COMPACT STRUCUTRES WITH SIGNIFICANT SECONDARY
STRUCUTURE CONTENT (VAL60)
SUMMARY
• VAL60 SET IS REPRESENTATIVE OF REAL PROTEINS
(PROTEINS FOLDS SELECTED BY GEOMETRY AND SIMMETRY AND NOT BY CHEMISTRY OF THE SEQUENCE)
• KNOWN FOLDS FORM ONLY A SMALL FRACTION OF THE FULL DATABASE
• NATURAL FOLDS ARE CHARACTERIZED BY SMALL CONTACT ORDER
WHY
KINETIC ACCESSIBILITY
HIGHER CO HIGHER TENDENCY TO AGGREGATE?
APPLICATIONS
• REALISTIC DECOYS
• DESIGN NEW PROTEINS
• CHECK PREDICTIONS IN SYNTHETIC BIOLOGY
• MODELS FOR MISFOLDED STRUCTURES RELATED TO NEURODEGENERATIVE DISEASES
COLLABORATORS
• PILAR COSSIO (NIH WASHINGTON)
• ALESSANDRO LAIO (SISSA TRIESTE)
• DANIELE GRANATA (SISSA TRIESTE)
• FABIO PIETRUCCI (CECAM – LAUSANNE)
• AMOS MARITAN (PADOVA)
• ANTONIO TROVATO (PADOVA)
Plos Computational Biology vol.6 e 1000957 (2010)
Scientific Reports 2, Art. No. 351 (2012)
CORRELATION BETWEEN POTENTIAL ENERGY AND CONTACT ORDER FOR VAL60 AND ALA60 STRUCUTRES
Similarity between the VAL60 and CATH databases
CATH and VAL60 are explored with equal probability
Distribution of the radius of gyration for the VAL60, VAL60+WATER,ALA60 and CATH 55–65 sets of structures.
Cα RMSD distributions for the 30,000 VAL60 and the 1500 ALA60 minimized through SD.
Probability of finding a structure in the VAL60 trajectory for different CO classes.
Number of independent structures
Bias Exchange Metadynamics
S Piana, A Laio, A bias-exchange approach to protein folding JOURNAL OF PHYSICAL CHEMISTRY B, 111, 4553 (2007)
1) List all the collective variables2) Run in parallel several molecular dynamics each biased with a metadynamic potential3) Swaps of the configuration
IT IS AN APPROACH DESIGNED FOR ACCELATING RARE
EVENTS IN VERY COMPLEXES CASES IN WHICH THE
VARIABLES THAT ARE RELVANT FOR THE PROCESS
ARE MORE THAN 2 OR 3
Are compact hydrogen-bonded polypetide structures in one-to-
one correspondence with protein structures
from the Protein Data Bank (PDB)?
YES!?
PNAS 103, 2605-2010 (2006)
Homopolypeptide ( side chain:C-beta atoms) with a very minimal potential consisting of H-bonding, excluded volume, and a uniform, pairwise attractive potential between side chains.