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Proton binding to proteins: pK(a) calculations with explicit and implicit solvent models.

Thomas Simonson1, Jens Carlsson, David A Case

  • 1Laboratoire de Biochimie (UMR7654 du CNRS), Department of Biology, Ecole Polytechnique, 91128 Palaiseau, France. thomas.simonson@polytechnique.fr

Journal of the American Chemical Society
|April 1, 2004
PubMed
Summary

Molecular dynamics free energy simulations accurately predict protein pKa shifts. Implicit solvent models, like the generalized Born (GB) model, show promise for calculating these shifts, even with complex protein reorganizations.

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Area of Science:

  • Biophysics
  • Computational Chemistry
  • Protein Science

Background:

  • Ionizable residues are crucial for protein function.
  • Proton binding (pKa) reveals electrostatic interactions.
  • Accurate pKa prediction is essential for understanding protein behavior.

Purpose of the Study:

  • To compute pKa shifts for aspartate residues using molecular dynamics free energy simulations (MDFE).
  • To compare explicit solvent simulations with implicit solvent simulations using the generalized Born (GB) model.
  • To investigate protein reorganization effects on pKa shifts.

Main Methods:

  • Molecular dynamics free energy simulations (MDFE) with explicit and implicit (GB) solvents.
  • Calculation of proton pKa shifts for three aspartate side chains in two proteins.
  • Analysis of dielectric response and protein reorganization during ionization.

Main Results:

  • Explicit solvent simulations correctly predicted the direction of pKa shifts with AMBER and CHARMM force fields.
  • Nonlinear dielectric response was observed for some aspartates due to multiple substates or significant reorganization.
  • MDFE with GB solvent accurately described protein reorganization and showed good agreement with experimental data and explicit solvent simulations.

Conclusions:

  • MDFE, particularly with GB implicit solvent, is a powerful tool for pKa prediction, capturing complex protein dynamics.
  • Implicit solvent models offer a computationally efficient yet accurate alternative to explicit solvent for pKa calculations.
  • Understanding protein reorganization is key to accurate pKa prediction, especially for buried residues with large shifts.