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Related Concept Videos

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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Ligand Binding Sites02:40

Ligand Binding Sites

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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
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Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
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The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

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The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
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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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Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

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Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
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A Protocol for Computer-Based Protein Structure and Function Prediction
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Site Identification by Ligand Competitive Saturation-Biologics Approach for Structure-Based Protein Charge

Asuka A Orr1, Aoxiang Tao2, Olgun Guvench2

  • 1Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Baltimore, Baltimore, Maryland 21201, United States.

Molecular Pharmaceutics
|April 5, 2023
PubMed
Summary
This summary is machine-generated.

Predicting protein effective charge is crucial for therapeutics. A new method, SILCS-Biologics, accurately calculates this charge by considering ion interactions, improving protein stability and manufacturability.

Keywords:
Debye−Hückel−Henry chargebufferexcipientformulationionmolecular dynamicssalt

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Area of Science:

  • Biochemistry
  • Computational Biology
  • Pharmaceutical Sciences

Background:

  • Protein therapeutics often face aggregation and viscosity issues at high concentrations.
  • Protein charge significantly impacts stability, bioavailability, and manufacturability.
  • Traditional computational methods neglect ion contributions to effective protein charge.

Purpose of the Study:

  • To introduce SILCS-Biologics, a novel structure-based approach for predicting effective protein charge.
  • To validate SILCS-Biologics against experimental data in various salt environments.
  • To demonstrate the method's ability to account for complex solution environments.

Main Methods:

  • Extension of the site identification by ligand competitive saturation (SILCS) approach to biologics (SILCS-Biologics).
  • Mapping of 3D ion, buffer, and excipient binding and occupancy on protein surfaces.
  • Prediction of effective protein charge considering environmental factors and molecular interactions.

Main Results:

  • SILCS-Biologics accurately predicts effective protein charge across different salt conditions.
  • The method successfully models ion competition and interactions with buffers/excipients.
  • 3D ion binding site structures were generated, enabling further electrostatic analysis.

Conclusions:

  • SILCS-Biologics is a powerful tool for predicting effective protein charge.
  • The approach enhances understanding of protein-ion interactions influencing solubility and function.
  • This method has significant implications for protein therapeutic development and formulation.