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    Protein Structure Modeling

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    zchepe
    The document discusses protein structure modeling and comparative protein structure modeling. It provides context that the 3D structure of a protein provides more information than just the sequence. Comparative modeling is applicable to sequences that share similarity to known protein structures, and allows for modeling of sequences that do not have an experimentally determined structure. The key steps in comparative modeling include template identification, target-template alignment, model building, and model evaluation. Accuracy depends on having an appropriate template and correct alignment. Typical errors can include incorrect templates, misalignments, and distortions in aligned regions.

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    Protein Structure Modeling

    Uploaded by

    zchepe
    42 views21 pages
    The document discusses protein structure modeling and comparative protein structure modeling. It provides context that the 3D structure of a protein provides more information than just the sequence. Comparative modeling is applicable to sequences that share similarity to known protein structures, and allows for modeling of sequences that do not have an experimentally determined structure. The key steps in comparative modeling include template identification, target-template alignment, model building, and model evaluation. Accuracy depends on having an appropriate template and correct alignment. Typical errors can include incorrect templates, misalignments, and distortions in aligned regions.

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    Andras[1]

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    The document discusses protein structure modeling and comparative protein structure modeling. It provides context that the 3D structure of a protein provides more information than just the sequence. Comparative modeling is applicable to sequences that share similarity to known protein structures, and allows for modeling of sequences that do not have an experimentally determined structure. The key steps in comparative modeling include template identification, target-template alignment, model building, and model evaluation. Accuracy depends on having an appropriate template and correct alignment. Typical errors can include incorrect templates, misalignments, and distortions in aligned regions.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    42 views21 pages

    Protein Structure Modeling

    Uploaded by

    zchepe
    The document discusses protein structure modeling and comparative protein structure modeling. It provides context that the 3D structure of a protein provides more information than just the sequence. Comparative modeling is applicable to sequences that share similarity to known protein structures, and allows for modeling of sequences that do not have an experimentally determined structure. The key steps in comparative modeling include template identification, target-template alignment, model building, and model evaluation. Accuracy depends on having an appropriate template and correct alignment. Typical errors can include incorrect templates, misalignments, and distortions in aligned regions.

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    of 21

    Protein structure modeling

    Andrs Fiser
    Department of Biochemistry and Seaver Foundation Center for Bioinformatics Albert Einstein College of Medicine New York, USA

    Why is it useful to know the structure of a protein not only its sequence?
    The 3D structure is more informative than sequence because patterns in space are frequently more recognizable than patterns in sequence

    Evolution tends to conserve function and function depends more directly on structu than on sequence, structure is more conserved in evolution than sequence.

    Why Protein Structure Prediction?

    Y 2005 Sequences Structures 2,300,000 29,000

    We know the experimental 3D structure for ~1% of the protein sequences

    Principles of Protein Structure


    GFCHIKAYTRLIMVG
    Desulfovibrio vulgaris

    Anacystis nidulans

    folding Ab initio prediction

    evolution Fold Recognition Comparative Modeling

    Condrus crispus

    Anabaena 7120

    Protein structure modeling

    Ab initio prediction

    Comparative Modeling
    Applicable to those sequences only that share recognizable similarity to a template structure Fairly accurate ( <3 Ang RMSD), typically comparable to a low resolution X-ray experiment. Not limited by size

    Applicable to any sequence

    Not very accurate (>4 Ang RMSD),

    Attempted for proteins of <100 residues

    Accuracy and applicability are limited by our understanding of the protein olding problem

    Accuracy and applicability are rather limited by the number of known folds

    What makes comparative modeling possible

    A small difference in the sequence makes a small ifference in the structure

    II Protein structures are clustered into fold families

    Structural Genomics

    Characterize most protein sequences (red) based on related nown structures (green). The number of families is much smaller than the number of proteins

    Structural Genomics

    Definition: The aim of structural genomics is to put every protein sequence within modeling distance of a known protein structure.

    Size of the problem: There are a few thousand domain fold families. There are ~20,000 sequence families (30% sequence id).

    Solution: Determine protein structures for as many different families as possible. Model the rest of the family members using comparative modeling

    Comparative Protein Structure Modeling


    Ca RMSD (% EQV) 2 (50) 1 (80) 0 (100) Anacystis nidulans

    Flavodoxin family

    Anabaena 7120

    COMPARATIVE MODELING
    KIGIFFSTSTGNTTEVA

    Condrus crispus

    Desulfovibrio vulgaris

    Clostridium mp. 20 50 100

    Steps in Comparative Protein Structure Modelin


    START

    TARGET
    ASILPKRLFGNCEQTSDEGLK IERTPLVPHISAQNVCLKIDD VPERLIPERASFQWMNDK

    TEMPLATE

    Template Search Target Template Alignment Model Building Model Evaluation

    ASILPKRLFGNCEQTSDEGLKIERTPLVPHISAQNVCLKIDDVPERLIPE MSVIPKRLYGNCEQTSEEAIRIEDSPIV---TADLVCLKIDEIPERLVGE

    No

    OK?

    Yes
    END

    Steps in Comparative Protein Structure Modeling


    START Template Search Target Template Alignment Model Building Model Evaluation No

    Pattern recognition, heuristic searches (e.g. BLAST, FastA) Profile and iterative alignment methods (e.g. HMMs, PSI-BLAST) Structure based threading (e.g. THREADER, FUGUE, 3DPSSM)

    OK? Yes END

    Steps in Comparative Protein Structure Modeling


    START

    Template Search
    Target Template Alignment

    Dynamic Programming, Pairwise Alignmen Multiple Alignments, Profiles, HMMs Structure based approaches (Threading)

    Model Building Model Evaluation

    No

    OK?

    Yes
    END

    Steps in Comparative Protein Structure Modeling


    START

    Template Search
    Target Template Alignment

    Rigid Body Assembly (COMPOSER) Segment Matching (SEGMOD, 3DPSSM) Satisfaction of Spatial Restraints (MODELLE Integrated (NEST)

    Model Building Model Evaluation

    loop modeling, side chain modeling

    No

    OK?

    Yes
    END

    Steps in Comparative Protein Structure Modelin


    START

    Template Search
    Target Template Alignment

    Stereochemistry (PROCHECK, WHATCHEC Environment (Profiles3D, Verify3d) Statistical potentials based methods (PROSA

    Model Building Model Evaluation

    No

    Is the model reliable? A model is reliable when it is based on a correct template and on an approximately correct alignment.

    OK?

    Yes
    END

    Typical Errors in Comparative Models


    Incorrect template Misalignment

    MODEL X-RAY TEMPLATE

    Region without a template

    Distortion in correctly aligned regions

    Side chain packing

    omparing accuracies of experimental and theoretical approach

    Some Models Can Be Surprisingly Accurate (in Some Regions)

    24% sequence identity


    YJL001W

    25% sequence identity


    YGL203C

    1rypH

    1ac5

    His 488 Ser 176 Asp 383

    odeling structural consequences of a point mutation (Ser-Pro) in Zebrafish forkhead transcription factor Foxi1

    re-modelled wild type segments(6 and 7aa) and NMR: modelled mutated segments with each other (6 and 7aa): wild type and mutated segments (6 and 7 aa):

    RMSD 1.78 and 1.82 1.19 3.65 and 3.75

    Altered subunit communication in subfamilies of dUTPases


    Predicting features that are not present in the template
    H. sapiens

    ophila m.

    1. Active form usually is a trimer,

    each active site is formed by all three monomers.


    2. Comparison of models and X-ray

    oli

    Eq. inf. virus

    structures reveals two subclasses of dUTPases with different type of subunit interfaces.
    3. Altered character of subunit

    interfaces correlates with the suggested different functional mechanism: polar/charged surface is better adjusted for allosterism.

    Convergent evolution of Trichomonas vaginalis lactate dehydrogenase from malate dehydrogenase.


    Designing new enzyme specificity with the aid of comparative models

    1.

    Sequences are identif from the Trichomonas genome project

    2.

    Mutations were designed using the constructed 3D mode to switch specificity.

    Core histones of the amitochondriate protist, Giardia lamblia

    Confirming fold by energy evaluation of comparative models

    G.Lamblia H2A H2B H3 H4 X-ray

    1aoiC/G -4.74 -1.15 -1.35 -2.29

    1aoiD/H -3.42 -4.34 -0.61 -2.82

    1aoiA/E -0.64 -0.41 -2.38 -0.26

    1aoiB/F -2.77 -1.70 -0.41 -4.79

    -5.41/-5.09 -3.98/-4.05 -2.74/-2.39 -5.23/-4.42

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