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Proton Therapy Delivery and Its Clinical Application in Select Solid Tumor Malignancies
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Published on: February 6, 2019

Who cares for the protons?

Paul Czodrowski1

  • 1Merck KGaA, Computational Chemistry, Frankfurter Strasse 250, D-64293 Darmstadt, Germany. paul.czodrowski@merckgroup.com

Bioorganic & Medicinal Chemistry
|April 3, 2012
PubMed
Summary
This summary is machine-generated.

Standard protonation states can be misleading for protein-ligand interactions. Comparing PROPKA (protein pK(a)) and MCCE (multi-conformation continuum electrostatics) methods revealed that using both is crucial for accurately identifying atypical protonation states.

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Area of Science:

  • Computational chemistry
  • Structural biology
  • Drug discovery

Background:

  • Standard protonation states are often assumed in protein-ligand interaction analysis.
  • This assumption may not accurately reflect the actual protonation states, impacting binding predictions.

Purpose of the Study:

  • To evaluate the accuracy of standard protonation state assumptions in protein-ligand interactions.
  • To compare two pK(a) calculation methods: PROPKA and MCCE.
  • To assess the reliability of these methods in identifying atypical protonation states using the Binary Protonation States (BIPS) metric.

Main Methods:

  • Applied PROPKA and MCCE pK(a) calculation methods to five approved drugs with available protein-drug complex structures.
  • Utilized the Binary Protonation States (BIPS) metric to analyze the calculated pK(a) values.
  • Compared the results from both computational methods.

Main Results:

  • Both PROPKA and MCCE methods successfully identified most sites with atypical Binary Protonation States (BIPS).
  • A significant number of atypical BIPS values were missed when relying on only one of the pK(a) calculation methods.
  • The two methods showed agreement on the majority of atypical protonation sites.

Conclusions:

  • Relying on standard protonation states for protein-ligand interactions can be unreliable.
  • Employing both PROPKA and MCCE pK(a) calculation methods enhances the accuracy of identifying atypical protonation states.
  • Using multiple computational methods provides a more robust basis for interpreting protonation states in drug-target complexes.