Determination of a transition state at atomic resolution from protein engineering data

J Mol Biol. 2002 Nov 15;324(1):151-63. doi: 10.1016/s0022-2836(02)00944-0.

Abstract

We present a method for determining the structure of the transition state ensemble (TSE) of a protein by using phi values derived from protein engineering experiments as restraints in molecular dynamics simulations employing a realistic all-atom molecular mechanics energy function. The method uses a biasing potential to select an ensemble of structures having phi values in agreement with the experimental data set. An application to acylphosphatase (AcP), a protein for which phi values have been measured for 24 out of 98 residues, illustrates the approach. The properties of the TSE determined in this way are compared with those of a coarse-grained model obtained using a Monte Carlo (MC) sampling method based on a C(alpha) representation of the structure. The two TSEs determined at different structural resolution are consistent and complementary. While the C(alpha) model allows better sampling of the conformation space occupied by the transition state, the all-atom model offers a more detailed description of the structural and energetic properties of the conformations included in the TSE. The combination of low-resolution C(alpha) results with all-atom molecular dynamics simulations provides a powerful and general method for determining the nature of TSEs from protein engineering data.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Acid Anhydride Hydrolases / chemistry
  • Acid Anhydride Hydrolases / metabolism
  • Acylphosphatase
  • Computer Simulation
  • Models, Molecular*
  • Monte Carlo Method
  • Protein Conformation
  • Protein Engineering / methods*
  • Proteins / chemistry*
  • Proteins / genetics

Substances

  • Proteins
  • Acid Anhydride Hydrolases