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Related Concept Videos

Conserved Binding Sites01:49

Conserved Binding Sites

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 analyses the...
Conserved Binding Sites01:49

Conserved Binding Sites

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 analyses the...
Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

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 form...
Protein and Protein Structure02:15

Protein and Protein Structure

Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.
A protein's shape is critical to its function. For example, an enzyme can...
Induced-fit Model01:13

Induced-fit Model

Most chemical reactions in cells require enzymes—biological catalysts that speed up the reaction without being consumed or permanently changed. They reduce the activation energy needed to convert the reactants into products. Enzymes are proteins, that usually work by binding to a substrate—a reactant molecule that they act upon.
Enzymes exhibit substrate specificity, meaning that they can only bind to certain substrates. This is mainly determined by the shape and chemical characteristics of...
Protein-protein Interfaces02:04

Protein-protein Interfaces

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 polypeptide...

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Related Experiment Video

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Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
07:08

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

Published on: July 14, 2015

Orientation-dependent backbone-only residue pair scoring functions for fixed backbone protein design.

Andrew J Bordner1

  • 1Mayo Clinic, Scottsdale, AZ 85259, USA. bordner.andrew@mayo.edu

BMC Bioinformatics
|April 20, 2010
PubMed
Summary

New backbone-only scoring functions improve protein design accuracy. These residue pair potentials, considering all six degrees of freedom, outperform existing methods and enhance threading applications by incorporating homolog data.

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Area of Science:

  • Computational biology
  • Structural bioinformatics
  • Protein modeling

Background:

  • Empirical scoring functions are vital for protein structure modeling, often relying on side chain conformations.
  • Backbone-only scoring functions offer computational efficiency for protein design by bypassing complex structure optimization.
  • Accurate scoring necessitates considering residue pair relative positions and orientations, not just distances.

Purpose of the Study:

  • To develop and evaluate backbone-only residue pair scoring functions for fixed backbone protein design.
  • To compare the accuracy of scoring functions based on residue separation (1D), position (3D), and position-orientation (6D).
  • To investigate computational methods leveraging these scoring functions for improved protein threading and design.

Main Methods:

  • Utilized Gaussian Mixture Models to fit 3D and 6D residue pair distributions, unlike prior 2D spherical harmonic approaches.
  • Assessed scoring function performance using threading accuracy on a benchmark set of protein backbones.
  • Developed and tested methods for averaging scores over homologs and applying Belief Propagation for sequence design.

Main Results:

  • Threading accuracy increased progressively with scoring function dimensionality (1D, 3D, 6D), with 6D achieving the highest accuracy.
  • The 3D and 6D backbone-only functions surpassed side chain-dependent potentials from previous studies.
  • Averaging scores over homologs improved threading accuracy, particularly for transmembrane alpha-helices.
  • The 6D function-based design method demonstrated greater robustness to backbone perturbations than all-atom methods.

Conclusions:

  • Backbone-only residue pair scoring functions incorporating all six degrees of freedom provide superior accuracy in protein modeling.
  • Integrating homolog scores further enhances accuracy in threading applications.
  • These 6D scoring functions outperform side chain-dependent potentials, circumventing complex side chain prediction.
  • The developed scoring functions serve as an effective initial filter for protein design prior to all-atom modeling.