Dual folding pathways of an α/β protein from all-atom ab initio folding simulations

Abstract

Successful ab initio folding of proteins with both ␣-helix and ␤-sheet requires a delicate balance among a variety of forces in the simulation model, which may explain that the successful folding of any ␣ / ␤ proteins to within experimental error has yet to be reported. Here we demonstrate that it is an achievable goal to fold ␣ / ␤ proteins with a force field emphasizing the balance between the two major secondary structures. Using our newly developed force field, we conducted extensive ab initio folding simulations on an ␣ / ␤ protein full sequence design ͑FSD͒ employing both conventional molecular dynamics and replica exchange molecular dynamics in combination with a generalized-Born solvation model. In these simulations, the folding of FSD to the native state with high population ͑Ͼ64.2%͒ and high fidelity ͑C ␣ -Root Mean Square Deviation of 1.29 Å for the most sampled conformation when compared to the experimental structure͒ was achieved. The folding of FSD was found to follow two pathways. In the major pathway, the folding started from the formation of the helix. In the minor pathway, however, folding of the ␤-hairpin started first. Further examination revealed that the helix initiated from the C-terminus and propagated toward the N-terminus. The formation of the hydrophobic contacts coincided with the global folding. Therefore the hydrophobic force does not appear to be the driving force of the folding of this protein.

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

“…The folding mechanisms reproduced in the present study were consistent with the results from the preceding studies. For FSD‐EY, the microsecond‐order replica exchange MD simulations with the explicit solvent model have reported the two folding pathways that were consistent with our results from the implicit solvent model, that is, (1) the α‐helix part folded first and followed by the folding of the β‐sheet, and (2) formation of the β‐sheet preceded that of the α‐helix. For a total simulation time, this preceding study required 4.8 μs in total (240 ns with 20 replicas).…”

Kinetics and Thermodynamics of Protein Folding

“…Therefore, we decided to reparameterize the force field under the same solvation scheme (GB/SA) for a better balance of the two major secondary structures. Using the newly developed force field, we conducted ab initio folding of FSD with both CMD and REMD (Lei, Wang et al 2009). High accuracy folding was achieved in terms of both the best folded structure (0.8 Å RMSD) and the population of the folded conformation (64.2%).…”

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

“…[5][6][7][8][9] In some of the implicit water simulation studies, the backbone energy term in the amber ff99 force field were re-parameterized to improve the propensity of the secondary structures. 5,6 Recently, it was found that even without re-optimization, a combination of standard amber ff96 with GB implicit solvation models produce a reliable free energy landscape for 1FSD folding.…”

“…Interestingly, this pathway is consistent with a previously suggested pathway from allatom simulations with a GB implicit solvation model. [5][6][7] The other folding pathway (Path II), which is rather new, suggested the simultaneous formation of the secondary structural elements (α and β segments) and the hydrophobic tertiary core (U2→T2→N).…”