Extremely precise free energy calculations of amino acid side chain analogs: Comparison of common molecular mechanics force fields for proteins

By Michael R. Shirts, J. Pitera, William Swope, Vijay S. Pande. 2003

607 citations recorded by the source corpus.

Quantitative free energy computation involves both using a model that is sufficiently faithful to the experimental system under study (accuracy) and establishing statistically meaningful measures of the uncertainties resulting from finite sampling (precision). We use large-scale distributed computing to access sufficient computational resources to extensively sample molecular systems and thus reduce statistical uncertainty of measured free energies. In order to examine the accuracy of a range of common models used for protein simulation, we calculate the free energy of hydration of 15 amino acid side chain analogs derived from recent versions of the OPLS-AA, CHARMM, and AMBER parameter sets in TIP3P water using thermodynamic integration. We achieve a high degree of statistical precision in our simulations, obtaining uncertainties for the free energy of hydration of 0.02–0.05 kcal/mol, which are in general an order of magnitude smaller than those found in other studies. Notably, this level of precision is comparable to that obtained in experimental hydration free energy measurements of the same molecules. Root mean square differences from experiment over the set of molecules examined using AMBER-, CHARMM-, and OPLS-AA-derived parameters were 1.35 kcal/mol, 1.31 kcal/mol, and 0.85 kcal/mol, respectively. Under the simulation conditions used, these force fields tend to uniformly underestimate solubility of all the side chain analogs. The relative free energies of hydration between amino acid side chain analogs were closer to experiment but still exhibited significant deviations. Although extensive computational resources may be needed for large numbers of molecules, sufficient computational resources to calculate precise free energy calculations for small molecules are accessible to most researchers.

Subfields: Atomic and Molecular Physics, and Optics, Materials Chemistry, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/dbcec2e982d5bd1596a029846c268eb719f519fc

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Atomic and Molecular Physics, and Optics

1. David L. Mobley
2. Michael R. Shirts
3. Pavel V. Klimovich
4. W. V. van Gunsteren
5. Eric J. Sorin
6. Vijay S. Pande
7. Chris Oostenbrink
8. Sandeep Patel

In Materials Chemistry

1. Eric J. Sorin
2. Vijay S. Pande
3. John D. Chodera
4. Michael R. Shirts
5. David L. Mobley
6. Sandeep Patel
7. Charles L. Brooks III
8. N. V. D. Vegt

In Molecular Biology

1. David L. Mobley
2. Vijay S. Pande
3. Michael R. Shirts
4. John D. Chodera
5. Eric J. Sorin
6. Pavel V. Klimovich
7. W. V. van Gunsteren
8. Chris Oostenbrink

Citations in the corpus

• Exploring the helix-coil transition via all-atom equilibrium ensemble simulations. (2005, methodology): “, 2001) as well as the validation of solute and solvent force-field accuracy and applicability (Rhee et al., 2004; Shirts et al., 2003; Zagrovic and Pande, 2003a), by greatly increasing the possible sampling time used to evaluate the accuracy and predictive power of current models.”
• Guidelines for the analysis of free energy calculations (2015, background): “Specifically, to avoid situations when the derivative oU=ok (needed for the TI analysis) would have been discontinuous, the potential for LJ transformations is typically treated via the soft-core potential [2, 36, 39, 42].”
• Alchemical free energy methods for drug discovery: Progress and challenges (2011, methodology): “[98,99] used large-scale distributed computing to compute amino acid solvation free energies to high precision, allowing for a direct comparison of force fields.”
• FreeSolv: A database of experimental and calculated hydration free energies, with input files (2014, neutral): “interesting in part simply because they can be calculated extremely precisely from molecular simulations for many small molecules [32, 49], enabling quantitative comparison to experiment.”
• Fluctuating charge force fields: recent developments and applications from small molecules to macromolecular biological systems (2006, background): “This is much in the spirit of recent calculations of free energies of amino acid analogs [103,104] that have set the target for the accuracy to reproduce or better.”