Lecture 10 protein structure prediction

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Lecture 10 protein structure prediction
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A protein sequence
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A protein sequence

• gtgi22330039refNP_683383.1 unknown protein
  protein id At1g45196.1 Arabidopsis thaliana
• MPSESSYKVHRPAKSGGSRRDSSPDSIIFTPESNLSLFSSASVSVDRCSS
  TSDAHDRDDSLISAWKEEFEVKKDDESQNL
• DSARSSFSVALRECQERRSRSEALAKKLDYQRTVSLDLSNVTSTSPRVVN
  VKRASVSTNKSSVFPSPGTPTYLHSMQKGW
• SSERVPLRSNGGRSPPNAGFLPLYSGRTVPSKWEDAERWIVSPLAKEGAA
  RTSFGASHERRPKAKSGPLGPPGFAYYSLY
• SPAVPMVHGGNMGGLTASSPFSAGVLPETVSSRGSTTAAFPQRIDPSMAR
  SVSIHGCSETLASSSQDDIHESMKDAATDA
• QAVSRRDMATQMSPEGSIRFSPERQCSFSPSSPSPLPISELLNAHSNRAE
  VKDLQVDEKVTVTRWSKKHRGLYHGNGSKM
• RDHVHGKATNHEDLTCATEEARIISWENLQKAKAEAAIRKLEKYFPQMKL
  EKKRSSSMEKIMRKVKSAEKRAEEMRRSVL
• DNRVSTASHGKASSFKRSGKKKIPSLSGCFTCHVF

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Protein Structure
Heparin docking Red heparin blue central
domain Yellow C-terminal domain
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A Protein Structure
beta-sheet
alpha-helix
loop
core
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Domain and Folds

• A discrete portion of a protein assumed to fold
  independently of the rest of  the protein and
  possessing its own function.
• Most proteins have multi-domains.
• The core 3D structure of a domain is called a
  fold. There are only a few thousand possible
  folds.

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Protein Similarity Level

• Family
• The proteins in the same family are homologous at
  the sequence level.
• Super Family
• all members of the super family should have the
  same overall domain architecture, i.e., the same
  domains in the same order
• Fold
• The folds of two domains are similar.

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Protein Folding Problem

• A protein folds into a unique 3D structure
  under the physiological condition.
• Lysozyme sequence
• KVFGRCELAA AMKRHGLDNY
• RGYSLGNWVC AAKFESNFNT
• QATNRNTDGS TDYGILQINS
• RWWCNDGRTP GSRNLCNIPC
• SALLSSDITA SVNCAKKIVS
• DGNGMNAWVA WRNRCKGTDV
• QAWIRGCRL

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Relevance of Protein Structurein the Post-Genome
Era
structure
medicine
sequence
function
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Structure-Function Relationship

• Certain level of function can be found
  without structure. But a structure is a key to
  understand the detailed mechanism.
• A predicted structure is a powerful tool for
  function inference.

Trp repressor as a function switch
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Structure-Based Drug Design

• Structure-based rational drug design is still
  a major method for drug discovery.

HIV protease inhibitor
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Protein Structure Prediction

• Structure
• Traditional experimental methods
• X-Ray or NMR to solve structures
• generate a few structures per day worldwide
• cannot keep pace for new protein sequences
• Strong demand for structure prediction
• more than 30,000 human genes
• 10,000 genomes will be sequenced in the next 10
  years.
• Unsolved problem after efforts of two decades.

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Ab initio Structure Prediction

• An energy function to describe the protein
• bond energy
• bond angle energy
• dihedral angel energy
• van der Waals energy
• electrostatic energy
• Minimize the function and obtain the structure.
• Not practical in general
• Computationally too expensive
• Accuracy is poor

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Template-Based Prediction

• Structure is better conserved than sequence
• Structure can adopt a
• wide range of mutations.
• Physical forces favor
• certain structures.
• Number of fold is limited.
• Currently 700
• Total 1,000 10,000 TIM
  barrel

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Scope of the Problem

• 90 of new globular proteins share similar folds
  with known structures, implying the general
  applicability of comparative modeling methods for
  structure prediction
• general applicability of template-based modeling
  methods for structure prediction (currently
  60-70 of new proteins, and this number is
  growing as more structures being solved)
• NIH Structural Genomics Initiative plans to
  experimentally solve 10,000 unique structures
  and predict the rest using computational methods

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Homology Modeling

• Sequence is aligned with sequence of known
  structure, usually sharing sequence identity of
  30 or more.
• Superimpose sequence onto the template, replacing
  equivalent sidechain atoms where necessary.
• Refine the model by minimizing an energy
  function.
• Applicable to 20 of all proteins.

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Concept of Threading

• Thread (align or place) a query protein sequence
  onto a template structure in optimal way
• Good alignment gives approximate backbone
  structure

Query sequence MTYKLILNGKTKGETTTEAVD
AATAEKVFQYANDNGVDGEWTYTE Template set
Prediction accuracy fold recognition / alignment
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4 Components of Threading

• Template library
• Scoring function
• Alignment
• Confidence assessment

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Core of a Template
Core secondary structures a-helices and
b-strands
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Definition of Template

• Residue type / profile
• Secondary structure type
• Solvent assessibility
• Coordinates for Ca / Cb
• RES 1 G 156 S 23 10.528 -13.223 9.932
  11.977 -12.741 10.115
• RES 5 P 157 H 110 12.622 -17.353 10.577
  12.981 -16.146 11.485
• RES 5 G 158 H 61 17.186 -15.086 9.205
  16.601 -15.457 10.578
• RES 5 Y 159 H 91 16.174 -10.939 12.208
  16.612 -12.343 12.727
• RES 5 C 160 H 8 12.670 -12.752 15.349
  14.163 -13.137 15.545
• RES 1 G 161 S 14 15.263 -17.741 14.529
  15.022 -16.815 15.733

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Energy (Score) Function
YKLILNGKTKGETTTEAVDAATAEKVFQYANDNGVDGEW
Pairwise energy How preferable to put two
particular residues nearby E_p
Singleton energy How well a residue fits a
template position (sequence and structural
environment) E_s
Alignment gap penalty E_g
Total energy E_p E_s E_g
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Threading problem

• Threading Given a sequence, and a fold
  (template), compute the optimal alignment score
  between the sequence and the fold.
• If we can solve the above problem, then
• Given a sequence, we can try each known fold, and
  find the best fold that fits this sequence.
• Because there are only a few thousands folds, we
  can find the correct fold for the given sequence.
• Threading is NP-hard.

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Computational Methods

• Branch and Bound.
• Integer Program.
• Use linear programming plus branch and bound.

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Blue Gene

• On December 6, 1999, IBM announced a 100 million
  research initiative to build the world's fastest
  supercomputer, "Blue Gene", to tackle fundamental
  problems in computational biology.
• More than one petaflop/s (1,000,000,000,000,000
  floating point operations per second)

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