Are Protein Force Fields Getting Better? A Systematic Benchmark on 524 Diverse NMR Measurements

By Kyle A. Beauchamp, Yu-Shan Lin, Rhiju Das, Vijay S. Pande. Journal of Chemical Theory and Computation, 2012

391 citations recorded by the source corpus.

Recent hardware and software advances have enabled simulation studies of protein systems on biophysically-relevant timescales, often revealing the need for improved force fields. Although early force field development was limited by the lack of direct comparisons between simulation and experiment, recent work from several labs has demonstrated direct calculation of NMR observables from protein simulations. Here we quantitatively evaluate recent molecular dynamics force fields against a suite of 524 chemical shift and J coupling (3JHNHα, 3JHNCβ, 3JHαC′, 3JHNC′, and 3JHαN) measurements on dipeptides, tripeptides, tetra-alanine, and ubiquitin. Of the force fields examined (ff96, ff99, ff03, ff03*, ff03w, ff99sb*, ff99sb-ildn, ff99sb-ildn-phi, ff99sb-ildn-nmr, CHARMM27, OPLS-AA), two force fields (ff99sb-ildn-phi, ff99sb-ildn-nmr) combining recent side chain and backbone torsion modifications achieve high accuracy in our benchmark. For the two optimal force fields, the calculation error is comparable to the uncertainty in the experimental comparison. This observation suggests that extracting additional force field improvements from NMR data may require increased accuracy in J coupling and chemical shift prediction. To further investigate the limitations of current force fields, we also consider conformational populations of dipeptides, which were recently estimated using vibrational spectroscopy.

Subfields: Materials Chemistry, Molecular Biology, Spectroscopy

View Paper: https://www.semanticscholar.org/paper/15d71c8fb4635b376714278e6cfd9f97ee90daf5

How researchers see this paper

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

In Materials Chemistry

In Molecular Biology

In Spectroscopy

Citations in the corpus

Efficient consideration of coordinated water molecules improves computational protein-protein and protein-ligand docking discrimination (2019, background): “Such a cost may be alleviated through the use of an implicit solvent[4] model, which while more efficient, incurs a loss of accuracy by disregarding the energetics of highly-coordinated water molecules[5].”
Developing a molecular dynamics force field for both folded and disordered protein states (2018, background): “Chou JJ, Case DA, Bax A (2003) Insights into the mobility of methyl-bearing side chains in proteins from (3)J(CC) and (3)J(CN) couplings.”