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Related Concept Videos

Ligand Binding Sites02:40

Ligand Binding Sites

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 Sites02:40

Ligand Binding Sites

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...
The Equilibrium Binding Constant and Binding Strength02:18

The Equilibrium Binding Constant and Binding Strength

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:
Phase II Reactions: Methylation Reactions01:17

Phase II Reactions: Methylation Reactions

Methylation is a phase II biotransformation process involving the attachment of a methyl group to a substrate. Enzymes known as methyltransferases orchestrate this reaction.
The mechanism of methylation unfolds in two stages. The first stage sees a methyltransferase enzyme facilitating the transfer of a methyl group from S-adenosylmethionine (SAM) to the substrate, forming S-adenosylhomocysteine (SAH). The second stage involves further metabolism of SAH into homocysteine, which can be recycled...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

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 the...
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.

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Related Experiment Video

Updated: May 23, 2026

Sequence-specific Labeling of Nucleic Acids and Proteins with Methyltransferases and Cofactor Analogues
12:07

Sequence-specific Labeling of Nucleic Acids and Proteins with Methyltransferases and Cofactor Analogues

Published on: November 22, 2014

Methyl effects on protein-ligand binding.

Cheryl S Leung1, Siegfried S F Leung, Julian Tirado-Rives

  • 1Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA.

Journal of Medicinal Chemistry
|April 17, 2012
PubMed
Summary

Adding a methyl group to drug compounds can significantly boost biological activity. This study found that such modifications, especially when burying the methyl group in hydrophobic pockets, frequently enhance drug potency.

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Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins
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Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins

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Profiling of Methyltransferases and Other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS)
17:12

Profiling of Methyltransferases and Other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS)

Published on: December 20, 2010

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Sequence-specific Labeling of Nucleic Acids and Proteins with Methyltransferases and Cofactor Analogues
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Published on: November 22, 2014

Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins
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Methods to Identify the NMR Resonances of the 13C-Dimethyl N-terminal Amine on Reductively Methylated Proteins

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Profiling of Methyltransferases and Other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS)
17:12

Profiling of Methyltransferases and Other S-adenosyl-L-homocysteine-binding Proteins by Capture Compound Mass Spectrometry (CCMS)

Published on: December 20, 2010

Area of Science:

  • Medicinal Chemistry
  • Computational Chemistry
  • Structural Biology

Background:

  • Methyl group addition is a common strategy in drug design to modulate biological activity.
  • Literature analysis of over 2000 cases indicates a notable frequency of activity enhancement.
  • Significant improvements are rare but warrant in-depth investigation.

Purpose of the Study:

  • To analyze the impact of methyl group addition on lead compound biological activity.
  • To investigate the molecular basis for significant activity boosts (≥100-fold).
  • To elucidate the role of protein-ligand interactions, water molecule distribution, and conformational energetics.

Main Methods:

  • Literature analysis of >2000 cases to determine frequency of activity boost.
  • In-depth analysis of four cases with a 100-fold activity increase.
  • Monte Carlo/free-energy perturbation (MC/FEP) calculations for methyl replacements.
  • Analysis of protein-ligand binding, water distribution, and conformational energetics.

Main Results:

  • An activity boost of ≥10-fold occurs in 8% of cases.
  • A 100-fold activity boost is observed in approximately 0.5% of cases (1 in 200).
  • Ortho-methyl substitutions can induce favorable conformational changes, enhancing activity.
  • Maximal activity gains result from combining conformational benefits with hydrophobic methyl group burial.

Conclusions:

  • Methyl group addition is a viable strategy for enhancing drug potency.
  • Favorable conformational changes and hydrophobic interactions are key drivers of significant activity improvements.
  • Computational methods like MC/FEP are valuable for understanding these effects and guiding drug design.