6.1
Ligand Binding Sites
Activities of most proteins depend on their interactions with other molecules or ions, known as ligands. Although ligands are able to bind to proteins, not every ligand binds to every protein.
Instead, a ligand binds only to a specific region on a protein’s surface called the binding site. But how do ligand binding sites ensure selectivity when proteins sit in a mixed ligand soup?
The particular arrangement of amino acids in a protein forms a complementary binding site on its surface for a specific ligand. However, complementary shapes are not enough for ligand binding.
Chemical interactions hold the ligand and the protein together. Generally, these interactions are non-covalent, reversible, and weak. Therefore, many of these interactions need to occur simultaneously during ligand binding.
For example, the larger the surface area of interaction, the more Van der Waals interactions can happen. These forces work best for large ligands. For others, the specific conformation of the binding site enables hydrogen bonding or electrostatic interactions.
But if the ligand binding site can form hydrogen bonds, why doesn’t it form hydrogen bonds with the water in its surroundings? The answer lies in the shape of the ligand binding site.
As an example, in this protein, the orientation of the amino acids forms a cavity, which restricts the access of water molecules. For individual water molecules, entering the cavity is energetically unfavorable as they have to break their hydrogen bonds with other water molecules.
Yet, the ligand will readily form hydrogen bonds with the polar amino acids in the binding site because the specific protein-ligand interactions are energetically more favorable than their interactions with water molecules.
Polar amino acids also form electrostatic interactions with a ligand. For instance, the negatively-charged glutamate in this binding site attracts the positively-charged ligand. A mutation in this sequence that turns this negatively charged glutamate into a positively charged lysine eliminates ligand binding.
Taken together, the exact sequence and orientation of the amino acids relative to each other determine the chemical reactivity and selectivity of the ligand binding site.
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 ligand-binding site. The specificity of a protein’s ligand-binding site is determined by the arrangement of its amino acid chain which gives the area its shape and chemical reactivity. Hence, a ligand-binding site provides a complementary shape to its ligand and keeps the ligand in place via chemical interactions. These chemical interactions are often noncovalent; however, since these interactions are reversible and weak, many of these interactions need to occur simultaneously to hold the protein and the ligand together.
Research that elucidates interaction mechanisms at ligand binding sites generally involves in silico modeling and in vitro approaches. In silico modeling uses computers to compare previously known protein structures and evolutionary data to make predictions to determine the optimal binding shape and energy state of the protein-ligand complex. In vitro approaches compliment in silico predictions by providing evidence for ligand binding through binding and kinetic assays in the laboratory. Ligand binding research is important for understanding the functions of proteins and how they perform specific cellular processes in both healthy, as well as in diseased conditions. For instance, certain genetic conditions and cancers can alter the sequence of a protein, ultimately affecting its ability to bind a ligand. In addition, this research also allows scientists to design drugs with specific interactions and minimal side effects by targeting the ligand-binding site of an implicated protein.
Activities of most proteins depend on their interactions with other molecules or ions, known as ligands. Although ligands are able to bind to proteins, not every ligand binds to every protein.
Instead, a ligand binds only to a specific region on a protein’s surface called the binding site. But how do ligand binding sites ensure selectivity when proteins sit in a mixed ligand soup?
The particular arrangement of amino acids in a protein forms a complementary binding site on its surface for a specific ligand. However, complementary shapes are not enough for ligand binding.
Chemical interactions hold the ligand and the protein together. Generally, these interactions are non-covalent, reversible, and weak. Therefore, many of these interactions need to occur simultaneously during ligand binding.
For example, the larger the surface area of interaction, the more Van der Waals interactions can happen. These forces work best for large ligands. For others, the specific conformation of the binding site enables hydrogen bonding or electrostatic interactions.
But if the ligand binding site can form hydrogen bonds, why doesn’t it form hydrogen bonds with the water in its surroundings? The answer lies in the shape of the ligand binding site.
As an example, in this protein, the orientation of the amino acids forms a cavity, which restricts the access of water molecules. For individual water molecules, entering the cavity is energetically unfavorable as they have to break their hydrogen bonds with other water molecules.
Yet, the ligand will readily form hydrogen bonds with the polar amino acids in the binding site because the specific protein-ligand interactions are energetically more favorable than their interactions with water molecules.
Polar amino acids also form electrostatic interactions with a ligand. For instance, the negatively-charged glutamate in this binding site attracts the positively-charged ligand. A mutation in this sequence that turns this negatively charged glutamate into a positively charged lysine eliminates ligand binding.
Taken together, the exact sequence and orientation of the amino acids relative to each other determine the chemical reactivity and selectivity of the ligand binding site.
- Protein-ligand interaction - This term describes the binding of a ligand to a protein.
- Ligand - A molecule that binds to another, often larger, molecule.
- Binding Site - The location on a protein where a ligand binds.
- Receptor – It is a protein that a ligand binds to, triggering a specific response.
- Protein-Ligand Binding Assay - A method to determine the interaction between a protein and its ligand.
- Define Protein-Ligand Interaction – Describe interaction of ligand and protein (e.g., protein-ligand interaction modeling).
- Contrast Ligand vs Protein – Discuss differences in nature and functions (e.g., are all ligands proteins, can proteins be ligands).
- Explore Binding Sites – Discuss locations and functions (e.g., where is the ligand binding site, what is a binding site).
- Explain Ligand Binding Assay – Procedure and interpretation of results.
- Apply in Context – Understand importance in cells and metabolism, drug development process.
- What is a protein-ligand interaction and how does it occur?
- What distinguishes ligands from proteins?
- What are binding sites and why are they crucial for protein-ligand interaction?
From Chapter 6:
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