Continuum Electrostatics Approaches to Calculating pKas and Ems in Proteins

Methods Enzymol. 2016;578:1-20. doi: 10.1016/bs.mie.2016.05.052. Epub 2016 Jun 20.


Proteins change their charge state through protonation and redox reactions as well as through binding charged ligands. The free energy of these reactions is dominated by solvation and electrostatic energies and modulated by protein conformational relaxation in response to the ionization state changes. Although computational methods for calculating these interactions can provide very powerful tools for predicting protein charge states, they include several critical approximations of which users should be aware. This chapter discusses the strengths, weaknesses, and approximations of popular computational methods for predicting charge states and understanding the underlying electrostatic interactions. The goal of this chapter is to inform users about applications and potential caveats of these methods as well as outline directions for future theoretical and computational research.

Keywords: Dielectric constant; Electrostatics; Molecular simulation; Monte Carlo; Poisson–Boltzmann; pK(a).

Publication types

  • Review
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Hydrogen-Ion Concentration
  • Kinetics
  • Ligands
  • Mathematical Computing
  • Molecular Dynamics Simulation*
  • Oxidation-Reduction
  • Protein Binding
  • Proteins / chemistry*
  • Protons*
  • Static Electricity
  • Thermodynamics


  • Ligands
  • Proteins
  • Protons