Probing α/β Balances in Modified Amber Force Fields from a Molecular Dynamics Study on a ββα Model Protein (1FSD)

Abstract

1FSD is a 28-residue designed protein with a ββα motif. Since this protein displays most essential features of protein structures in such a small size, this model protein can be an outstanding system for evaluating the balance in the propensity of the secondary structures and the quality of all-atom protein force fields. Particularly, this protein would be difficult to fold to its correct native structure without establishing proper balances between the secondary structure elements in all-atom energy functions. In this work, a series of the recently optimized five amber protein force fields [ff03*, ff99sb*-ildn, ff99sb-φ'-ildn, ff99sb-nmr1-ildn, ff99sb-ΦΨ(G24, CS)-ildn] were investigated for the simulations of 1FSD using a conventional molecular dynamics (MD) and a biased-exchange meta-dynamics (BEMD) methods. Among those tested force fields, we found that ff99sb-nmr1-ildn and ff99sb-ΦΨ(G24, CS)-ildn are promising in that both force fields can locate the native state of 1FSD with a high accuracy (backbone rmsd ≤ 1.7 Å) in the global free energy minimum basin with a reasonable energetics conforming to a previous circular dichroism (CD) experiment. Furthermore, both force fields led to a common set of two distinct folding pathways with a heterogeneous nature of the transition state to the folding. We anticipate that these force fields are reasonably well balanced, thereby transferable to many other protein folds.

Folding of a Zinc-Finger ββα-Motif Investigated Using Two-Dimensional and Time-Resolved Vibrational Spectroscopy

“…Previous experimental ,, and theoretical − investigations of FSD-1 have reached different conclusions regarding its folding and unfolding mechanism. In particular, the nature of the melting transition (e.g., whether the folding and unfolding occur cooperatively or through intermediates) and the stages of folding in which the different secondary and tertiary structural elements are formed are subject of debate.…”

An Updated Test of AMBER Force Fields and Implicit Solvent Models in Predicting the Secondary Structure of Helical, β-Hairpin, and Intrinsically Disordered Peptides

“…Nevertheless, except for some studies, ,− the comparison of force field accuracy in predicting peptide folding behavior has been focused on a limited number of test systems. ,,− Furthermore, with some exceptions, ,, current force fields have been validated focusing on α-helix and β-hairpin secondary structures, with less attention being paid to intrinsically disordered peptides (IDPs), − ,, principally performing the simulations in explicit solvent. ,,,,− ,,,,, Concerning this latter aspect, REMD simulation time dramatically increases in explicit solvent conditions; thus, large CPU power is needed when simulating long peptides or a large number of systems. Therefore, in drug discovery, the use of an implicit solvent model may be advantageous, as long as the accuracy in predicting secondary structures is maintained. − …”

Common folding processes of mini-proteins: Partial formations of secondary structures initiate the immediate protein folding

“…For instance, to address the force field parameter dependences, several parameter sets were investigated as hybrid‐type force fields by mixing different parameter sets for the ββα‐type mini‐proteins. As examples, optimized parameter sets for an analogous ββα‐type mini‐protein (PDBid: 1FSD) were proposed and the structural stability of native state was investigated in terms of the newly updated parameter sets . Judging from the previous studies, it might be difficult to quantitatively evaluate the structural stability of the native state of the ββα‐type mini‐protein, FSD‐EY.…”