Folding free energy landscapes of β-sheets with non-polarizable and polarizable CHARMM force fields

“…Consistently, the average Rg of CFFs is also smaller than that of PFFs (data listed in Table ). It is in agreement with previous contributions reporting that unfolded states are over collapsed in CFFs and that more extended conformations can be sampled in simulations of Drude PFF. ,,, …”

“…While the Drude-2013 FF has shown success in reproducing experimental observables in simulations up to 1 μs, there were also some limitations. In particular, β-sheet structures in simulations longer than 100 ns displayed some instability in simulations in our laboratory (Figure below) as well as in a published study . Additionally, MD simulations for a number of proteins based on the Drude-2013 model typically yielded larger root-mean-square (RMS) differences relative to crystal structures as compared to the additive CHARMM36 FF .…”

“…The third minimum, corresponding to the native β-hairpin conformation, is located in a broader region with 3 < N H < 5 and R Gyr ≃ 7. It is important to recall at this point that the relative free energy values of these three minima are known to depend strongly on the choice of the force field employed in the simulations. , The Amber03 force field, employed here for consistency with the 4DAR5 simulations, overestimates α-helices over other secondary structures, which causes the free energy landscape of GB1 to be deeper at N H < 1 than in the β-hairpin region, where the global minimum should in fact be located . Nevertheless, this known and expected inconsistency does not hinder our further analysis, in which CD spectra pertinent to ensembles of conformers constrained in local regions of the sampled phase space are calculated.…”