Order through Disorder: Hyper-Mobile C-Terminal Residues Stabilize the Folded State of a Helical Peptide. A Molecular Dynamics Study

2011

Biophysical Journal

Slowly but steadily bibliographic evidence is accumulating that the apparent convergence of the various biomolecular force fields as evidenced from simulations of proteins in the folded state does not hold true for folding simulations. Here we add one more example to the growing list of peptides and proteins for which different force fields show irreconcilable differences in their folding predictions, even at such a fundamental level as that of a peptide's secondary structure. We show that for an undecamer peptide that is known from two independent NMR structure determinations to have a mainly 3(10)-helical structure in solution, three mainstream biomolecular force fields give completely disparate predictions: The CHARMM force field (with the CMAP correction) predicts an outstandingly stable α-helical structure, in disagreement not only with the experimental structures, but also with experimental evidence obtained from circular dichroism. OPLS-AA shows an almost totally disordered peptide with the most frequently observed folded conformation corresponding to a β-hairpin-like structure, again in disagreement with all available experimental evidence. Only the AMBER99SB force field appears to qualitatively agree with not only the general structural characteristics of the peptide (on the account of both NMR- and CD-based experiments), but to also correctly predict some of the experimentally observed interactions at the level of side chains. Possible interpretations of these findings are discussed.

Section: Discussionsupporting

confidence: 89%

Section: Force Fields System Preparation and Simulation Protocolmentioning

confidence: 99%

Three Force Fields' Views of the 310 Helix

Patapati

2011

Biophysical Journal

“…dynamics of a wide variety of peptide systems. Our perspective on the current literature is that among all extensively tested and validated force fields [25], the AMBER99SB family of force fields and particularly the 99SB � -ILDN and-to a lesser extent-the 99SB-ILDN variants [26][27][28][29] show an outstanding performance against a wide range of systems, from very stable folders [26][27][28][29][30][31] to marginally stable peptides [30][31][32][33][34][35][36][37], and for every structural motif, from mainly helical [27][28][29][31][32][33] to almost exclusively β-hairpin-like [29,31,[37][38][39]. In this communication, we attempt to examine the accuracy of MD simulations and their ability to reproduce the results derived from the aforementioned DFT calculations (of ref 24), as well as experimental data (i.e., Thornton's criteria) [1].…”

Section: Plos Onementioning

confidence: 99%

“…In order to study the propensities of the Asn-Gly segment to form β-turn structures we conducted three MD simulations for the same three capped heptapeptides that Kang and Yoo used in their work: Ac-Ala-Ala-Asn-Gly-Ala-Ala-NHMe (hp NG -1), Ac-Leu-Val-Asn-Gly-Gln-Tyr-NHMe (hp NG -2, from PDB entry 1EST) [44] and Ac-Phe-Val-Asn-Gly-Leu-Phe-NHMe (hp NG -3, derived from an octapeptide with the similar sequence Boc-Leu-Phe-Val-Aib-D-Ala-Leu-Phe-Val-OMe that forms a type I' Aib-D-Ala β-turn) [45]. The system preparation procedure and simulation protocol have been previously described [30][31][32][33][34][35][36][37][38] and in summary were performed as follows. Starting from the fully extended states, addition of missing hydrogen atoms and solvation-ionization were performed with the LEAP program from the AMBER tools distribution.…”

Section: System Preparation and Simulation Protocolsmentioning

confidence: 99%

A molecular dynamics simulation study on the propensity of Asn-Gly-containing heptapeptides towards β-turn structures: Comparison with ab initio quantum mechanical calculations

Mitsikas

2020

PLoS ONE

Self Cite

Both molecular mechanical and quantum mechanical calculations play an important role in describing the behavior and structure of molecules. In this work, we compare for the same peptide systems the results obtained from folding molecular dynamics simulations with previously reported results from quantum mechanical calculations. More specifically, three molecular dynamics simulations of 5 μs each in explicit water solvent were carried out for three Asn-Gly-containing heptapeptides, in order to study their folding and dynamics. Previous data, based on quantum mechanical calculations within the DFT framework have shown that these peptides adopt β-turn structures in aqueous solution, with type I’ β-turn being the most preferred motif. The results from our analyses indicate that at least for the given systems, force field and simulation protocol, the two methods diverge in their predictions. The possibility of a force field-dependent deficiency is examined as a possible source of the observed discrepancy.

“…To our knowledge, there is not a single example of a stably folded peptide for which the combination of the AMBER99SB‐ILDN (or AMBER99SB‐STAR‐ILDN) force field with TIP3P water model and full electrostatics has failed to correctly identify the peptide's native state. To the contrary, the aforementioned combination has been shown to be able to accurately predict the structure and dynamics of peptides ranging from very stable folders, to marginally stable peptides, and for all structural motifs from mainly helical to almost exclusively β‐hairpin like . It should be noted, however, that recent studies have indicated the presence of a tendency of these force fields to produce overly compact structures in the case of disordered peptide systems which are known to be rather difficult systems to study with empirical force fields .…”

Section: Introductionmentioning

confidence: 99%

Characterizing a partially ordered miniprotein through folding molecular dynamics simulations: Comparison with the experimental data

Baltzis

2015

Protein Science

Self Cite

The villin headpiece helical subdomain (HP36) is one of the best known model systems for computational studies of fast-folding all-a miniproteins. HP21 is a peptide fragment-derived from HP36-comprising only the first and second helices of the full domain. Experimental studies showed that although HP21 is mostly unfolded in solution, it does maintain some persistent nativelike structure as indicated by the analysis of NMR-derived chemical shifts. Here we compare the experimental data for HP21 with the results obtained from a 15-ls long folding molecular dynamics simulation performed in explicit water and with full electrostatics. We find that the simulation is in good agreement with the experiment and faithfully reproduces the major experimental findings, namely that (a) HP21 is disordered in solution with <10% of the trajectory corresponding to transiently stable structures, (b) the most highly populated conformer is a native-like structure with an RMSD from the corresponding portion of the HP36 crystal structure of <1 Å , (c) the simulationderived chemical shifts-over the whole length of the trajectory-are in reasonable agreement with the experiment giving reduced v 2 values of 1.6, 1.4, and 0.8 for the Dd 13 C a , Dd 13 CO, and Dd 13 C b secondary shifts, respectively (becoming 0.8, 0.7, and 0.3 when only the major peptide conformer is considered), and finally, (d) the secondary structure propensity scores are in very good agreement with the experiment and clearly indicate the higher stability of the first helix. We conclude that folding molecular dynamics simulations can be a useful tool for the structural characterization of even marginally stable peptides.