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Hydroxyl and water molecule orientations in trypsin: comparison to molecular dynamic structures
1Department of Bioorganic Chemistry, Genentech Inc., South San Francisco, California 94080, USA.
Basic Life Sciences
|January 1, 1996
Summary
Molecular dynamics simulations accurately predict hydroxyl hydrogen positions in trypsin, validating force-field models for protein hydrogen interactions. This study advances understanding of water molecule behavior within protein structures.
Area of Science:
- Structural Biology
- Computational Biophysics
- Biomolecular Simulation
Background:
- Neutron diffraction uniquely determines hydrogen and deuterium positions in large molecules like proteins.
- Understanding hydrogen atom behavior is crucial for accurate molecular modeling and predicting protein function.
Purpose of the Study:
- To compare experimentally observed hydrogen positions in trypsin with molecular dynamics (MD) simulation results.
- To evaluate the accuracy of standard force-field approaches in describing hydrogen atom orientations and interactions.
Main Methods:
- A 140 picosecond (ps) all-atom molecular dynamics simulation using the AMBER force-field was performed on trypsin.
- Neutron density maps derived from D2O-H2O difference Fourier maps were used for experimental data.
- A novel method was developed to create pseudo-density maps from simulation data for direct comparison.
Main Results:
- Simulated hydroxyl hydrogen orientations closely matched experimental neutron density data, with most within one standard deviation.
- The simulation accurately predicted shifted hydroxyl group rotamers not typically considered 'standard'.
- Agreements were observed for well-ordered water molecules; broadened neutron density profiles correlated with complex hydrogen bonding networks in simulations.
Conclusions:
- Standard force-field MD simulations can adequately represent the local electrostatic and van der Waals forces governing hydroxyl hydrogen orientations in proteins.
- The electrostatic environment, not just cavity size, dictates the behavior of internal water molecules.
- The developed comparison method effectively bridges discrete simulation observations with time-averaged diffraction data, aiding analysis of disordered water molecules.