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Related Concept Videos

Protein Folding01:25

Protein Folding

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Proteins are chains of amino acids linked together by peptide bonds. Upon synthesis, a protein folds into a three-dimensional conformation, critical to its biological function. Interactions between its constituent amino acids guide protein folding, and hence the protein structure is primarily dependent on its amino acid sequence.
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
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Protein Organization01:24

Protein Organization

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Proteins are polymers of amino acid residues. They are versatile and responsible for different cellular functions, including DNA replication, molecular transport, catalysis, and structural support. Proteins have a hierarchical structure comprising at least three levels of organization: primary, secondary, and tertiary structure. Some large proteins have a quaternary structure where individual protein subunits are linked together.
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Molecular Chaperones and Protein Folding03:00

Molecular Chaperones and Protein Folding

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The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...
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Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

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Protein domains are small structurally independent units that are part of a single amino acid chain.  Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
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Conserved Binding Sites01:49

Conserved Binding Sites

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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
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Protein-protein Interfaces02:04

Protein-protein Interfaces

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Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
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Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules

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Knowledge-Based Unfolded State Model for Protein Design.

Vaitea Opuu1, David Mignon1, Thomas Simonson2

  • 1Laboratoire de Biologie Structurale de la Cellule (CNRS UMR7654), Ecole Polytechnique, Palaiseau, France.

Methods in Molecular Biology (Clifton, N.J.)
|March 17, 2022
PubMed
Summary
This summary is machine-generated.

This study introduces a new computational framework for designing stable proteins. The method optimizes protein sequences by maximizing the likelihood of sampling native-like structures, improving protein design efficiency.

Keywords:
Implicit solventMachine learningMaximum likelihoodMolecular mechanicsMonte CarloPDZ domainProteus software

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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
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Area of Science:

  • Computational biology
  • Protein engineering
  • Biophysics

Background:

  • Protein stability is crucial for function, requiring a significant free energy difference between folded and unfolded states.
  • The unfolded state's energy, influenced by sequence composition, is key for accurate protein design.
  • Current models often simplify unfolded state interactions, limiting design precision.

Purpose of the Study:

  • To develop a computational framework for designing stable proteins and miniproteins.
  • To optimize protein sequences by maximizing the probability of sampling native-like conformations.
  • To present an iterative algorithm within the Proteus software for protein design.

Main Methods:

  • Utilizing an extended peptide model for the unfolded state, parametrized by sequence composition.
  • Employing a Monte Carlo procedure to explore sequence space and Boltzmann probability distributions.
  • Combining an unfolded state model with a folded state model using molecular mechanics and Generalized Born solvent.

Main Results:

  • Developed an iterative algorithm following the likelihood gradient for protein sequence optimization.
  • Optimized the model for three PDZ domains and successfully redesigned them.
  • Generated native-like protein sequences, consistent with recent experimental validation studies.

Conclusions:

  • The presented maximum likelihood framework offers a robust approach to protein design.
  • The Proteus software and tutorial provide a practical tool for researchers in protein engineering.
  • The method demonstrates potential for designing stable and functional protein variants.