Marziyeh Movahedi

Master of Computer science, Amirkabir university University.

Movahedi, Marziyeh, Fatemeh Zare-Mirakabad, and Seyed Shahriar

Arab. "Evaluating the accuracy of protein design using native

secondary sub-structures." BMC bioinformatics 17.1 (2016): 353.

Computational Challenges in Proteins

Marziyeh Movahedi

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C-Terminus

N-Terminus

1 2

Cα

Ala-Gln-Ile-Leu-Met-Phe-Pro-Trp-Val-Arg-Asn-Asp-Cys-Glu-Gly-His-Lys-Ser-Thr-Tyr-Sec-Pyl

Hidrophile Hydrophobe

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Dihedral Angles

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Rotamer

6

انواع ساختارها

آلفا بتا (، گاما و بتا)پیچش...

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Protein Structure

α - helix

β - sheet

Random coil

Num of residue Hydrogen bonding

α-helix 3.6 i + 4 → i

π-helix 4.4 i + 5 → i

310 helix 3 i + 3 → i

Parallel

Anti Parallel

Primary Structure Secondary Structure Super Secondary Structure

β - Turn Helix Beta Sheet

β – Hairpin

Greek key

Tertiary (3D) Structure Quaternary Structure

Protein Subunit

Hemoglobine

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Three Main Protein Classes

Globular Protein

Membrane Protein

Fibrous Protein

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Protein Tertiary Structure Visualization

All-atom Ribbon Diagram Solvent Accessible

Surface Area Backbone N—Cα—C

Jmol RasMOL PyMOL

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Secondary Structure Prediction

MNSERSDVTLYQPFLDYAIAYMRS HHHBBCCCCHHHBBBCCHHBBBHH

Probabilistic Method GOR, Chou-Fasman 60%

Machine Learning Methods PSI-pred, PSS-pred

80%

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Inverse Secondary Structure Prediction

HHHBBCCCCHHHBBBCCHHBBBHH MNSERSDVTLYQPFLDYAIAYMRS

1. A feature of protein 3D structure => the protein function depends on it

2. Provides an outline of protein 3D structure

3. Affects the amino acids arrangement along through the evolution

GAPSSIF (2016)

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Tertiary Structure Prediction

MNSERSDVTLYQPFLDYAIAYMRS

Rosetta@Home

Modeller

I-TASSER

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Protein Design

1) Positive Design

2) Negative Design

The rational design of new protein molecules to fold to a target protein structure.

with the ultimate goal of designing novel function and/or behavior

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Protein Design applications

Enhance structural characteristics

Enzyme design

Drug Design

Protein resurfacing

Design of globular proteins

Design of trans-membrane proteins

Design of fibrous proteins

Biosensor

The bioremediation of waste streams

The production of bioplastics and biofuels

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Protein Design is computationally hard

V

A I

F

R P

Q C

W

Y

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Types of protein design problem

De novo Protein Design

Designing proteins from scratch with novel function/behavior

Input: Protein Backbone (N—Cα—C) - derived from natural proteins

Output: amino acid sequences

Protein Redesign (Resurfacing – Rotamer Design)

Aims to improve/create a desired property in known protein structure and sequences.

most of the residues are maintained wild-type just a few are allowed to mutate.

Input: All atom protein structure

Output: amino acid sequences

Full Design Problem

Aims to find an amino acid sequence that can interact with input structure

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Negative/Positive Design Flexibility in protein design

Amino Acids

20 standard amino acids

Mainly applies to

De novo design & Redesign

Side Chain

Continuous space for angles

Mainly applies to

Resurfacing & Rotamer Design

bond and dihedral

bond lengths

angles

Back Bone

Although rational protein design

must preserve the general

backbone, its flexibility is

important in special cases. Redesign , esp. Enzyme design.

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Negative/Positive Design The role of Rotamers

1 2

Difference in

surface

Negative Design

3 4

Difference in

Energy

Negative Design

The amino acid side-chains

are restricted to low-energy

conformations.

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Negative/Positive Design How to consider side chain flexibility?

Continuous space for angles reduces to discrete conformation for Rotamers. (How?)

Using Rotamer Libraries

Discrete sets of Rotamers are identified from known protein structures

Ideal Values for bond lengths and bond angles, while restricting dihedral angles to a few frequently

observed low-energy conformations

Dunbrack Rotamer Libraries

http://dunbrack.fccc.edu/

Backbone-dependent libraries

Backbone-Independent libraries

secondary-structure-dependent

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Negative/Positive Design How to consider back bone flexibility?

Allowing some backbone flexibility can significantly increase the number of sequences

How?

small and continuous global backbone movements

Discrete backbone samples around the target fold

Protein loop flexibility

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What is PDB?

Protein Data Bank

Since 1950

A repository for 3D biological macromolecular structure

Obtained by X-Ray crystallography

www.rcsb.org.pdb

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DSSP

Parsing PDB files

Define Secondary Structure of Proteins

Input atomic-resolution coordinates of the protein

Assigning secondary structure to the amino acids of a protein

DSSP does not predict secondary structure

Both database and program

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DSSP