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ICFF: a new method to incorporate implicit flexibility into an internal coordinate force field.
Vsevolod Katritch1, Maxim Totrov, Ruben Abagyan
1Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines, TPC-28, La Jolla, California 92037, USA.
Journal of Computational Chemistry
|December 24, 2002
Summary
A new Internal Coordinate Force Field (ICFF) method accurately projects Cartesian force fields onto molecular models, enabling faster geometry optimizations for applications like ligand docking and macromolecular modeling.
Area of Science:
- Computational Chemistry
- Molecular Modeling
- Biophysics
Background:
- Molecular modeling relies on accurate force fields to simulate molecular behavior.
- Cartesian force fields, while accurate, are computationally expensive due to a high number of variables.
- Internal coordinate systems offer reduced complexity but often sacrifice accuracy.
Purpose of the Study:
- To develop a novel method for projecting Cartesian force fields onto internal coordinate molecular models.
- To create an Internal Coordinate Force Field (ICFF) that approximates source Cartesian force fields.
- To enhance the efficiency of molecular modeling simulations, particularly geometry optimizations.
Main Methods:
- Developed an algorithm to automatically generate the ICFF from a Cartesian force field.
- Incorporated implicit flexibility by formulating empirical torsion energy as a sixfold Fourier series.
- Utilized a soft polynomial repulsion function for non-bonded interactions to mimic bond flexibility.
- Generated fixed covalent geometries compatible with the ICFF energy function.
- Implemented the ICFF algorithm using the MMFF94s Cartesian force field as the source.
Main Results:
- The ICFF method reduces model variables by at least 10-fold, accelerating geometry optimizations.
- Benchmarking on organic molecules showed ICFF accurately reproduces MMFF94s equilibrium conformational energy differences (RMSD ~0.64 kcal).
- Detailed torsion energy profiles were accurately reproduced by ICFF (RMSD ~0.37 kcal).
- Compared to rigid geometry models, ICFF significantly reduces estimation bias.
Conclusions:
- The ICFF method provides an accurate and computationally efficient alternative to traditional Cartesian force fields.
- Implicit flexibility in ICFF parameters allows for accurate representation of molecular conformations.
- This method is critical for applications requiring fast and accurate conformational sampling, such as flexible ligand docking and macromolecular modeling.