GB3 benchmarks  | @Chapin Cavender | JW (slide 11): have the simulations on this slide finished yet? CC: still unfinished – prioritised folded protein trajectories instead. JW: Ok, so these are identical to the plots from last meeting. CC: not expecting extended trajectories to change qualitative results, although maybe variation on the helicity of the peptide across residues
LS: did moving to the single-point workflow mean that the 15-mer no longer folds to a helix? JW: do you have a hypothesis why smaller benchmarks and larger benchmarks seem to show such different results? CC: we see that the unstructured peptides are often anticorrelated with larger benchmarks, maybe because they’re unstructured and don’t populate the alpha and beta basins LW: does this extend to the 15-mer finally folding to helices? CC: if we go back to free energy of beta to alpha, it might be that alpha structures are too stable and other factors are destabilising the alpha helix in the folded protein
PB: could it be nonbonded parameters? CC: haven’t ruled it out, but have been focusing on what other research groups have done, and most major bio FFs use same nonbonded terms as their small molecule FFs. I’ve seen other FFs modify their torsions and fix the problems CC: could try to work in nonbonded terms, e.g. by fitting to 15-mer simulations DM: another way to test this is to go to the Amber nonbonded parameters and try again? CC: I tried this with 0.0.2 FFs, swapped in 1. just charges, 2. both charges and LJ, neither variant gave helical content for 15-mer. Could just be you shouldn’t Frankenstein FFs. DM: what about re-fitting with Amber NBs? If it gives good results we can focus on nonbondeds. CC: fairly straightforward to do a reweighting to 15-mer without additional work, since I already have the scripts needed. I couldn’t do this before since our helical content was 0. Now that the Specific 0.0.3 has some helical content, we can reweight this to get rest of the helix correct.
LS: can you look, atom-by-atom, at the differences in energy between ff14sb and the SMIRNOFF candidates in the unfolding simulations? Perhaps there’s a particular LJ pair or charges that would become clear with this analysis CC: I have not looked an energy breakdown for those yet MS: entropy would also play a role though LS: CC previously mentioned torsions were pretty similar, basins pretty similar to 14sb, so expect that part of the energy to look similar. MS: not sure I agree MS: could take one simulation and re-evaluate with 14sb and see if there’s any particular configuration that’s particularly high or low energy. Or vice versa.
PB: if you had different results in different water models, would you attribute differences to torsions or nonbonded? LS (slide 17): are you checking that the total sum of alpha + beta matches what you expect? Could get similar ratios but poor populations. CC: will look at energy breakdowns between force fields (in both directions)
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