Direct computation of long time processes in peptides and proteins: Reaction path study of the coil‐to‐helix transition in polyalanine

BBL is an independent folding domain of a large multienzyme complex, 2-oxoglutarate dehydrogenase. The folding mechanism of BBL is under debate between the views of noncooperative downhill-type and classical two-state. Extensive replica exchange molecular dynamics simulations of BBL in explicit solvent have shown some non-two-state behaviors despite no definitive evidence of downhill folding. In this work, we postprocess the replica exchange data using our roadmap-based MaxFlux reaction path algorithm to reveal atomically detailed folding pathways. A connected graph is used to organize and visualize the folding pathways initiated from random coils. High structural and transition heterogeneity is seen in the early stage of folding. Two main parallel folding pathways emerge in the later stage; one path shows that tertiary contact and helix formation develop at different stages of folding, whereas the other path exhibits concurrence of secondary and tertiary structure formation to some extent. Because the native state of BBL is sensitive to experimental conditions, we speculate that the relative predominance of the two pathways may vary with the protein construct and solvent conditions, possibly leading to the seeming discrepancy of experimental results. Our roadmap-based reaction path algorithm is a general tool to extract path information from replica exchange.

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“…S4. Experimentally, Leu 9 , Arg 31 , and Val 34 are also found to be critical for stabilization of native structure (4).…”

Section: Emergence Of Nonlocal and Local Contactsmentioning

confidence: 96%

“…Our roadmap-based reaction-path algorithm has been successful in locating the folding pathway of b-hairpin (24) and engrailed homeodomain (23). Other implementations (28)(29)(30)(31) based on the same principle as the minimum resistance path or maximum reactive flux path (26) have also been shown useful.…”

Section: Theoretical Background Of Maxfluxmentioning

confidence: 96%

Observation of Two Families of Folding Pathways of BBL

Fan

Duan

et al. 2011

Biophysical Journal

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“…3 H-bonds play a relevant role in the stabilization of b-turn or 3 10 -helical conformations, the appearance of this type of intramolecular H-bonds suggested the presence of these two secondary structural elements. The important role of b-turns played in the nucleation of helical conformations is well-known, nevertheless, they appear as intermediate states during the transition processes from random coil to helices [48,49]. Similarly, the 3 10 -helical element can be also observed as an intermedier structure in the course of a-helix formation [50], furthermore, both the N-and C-terminal ends of a-helical segments are found to be often characterized by a 3 10 -helical conformation [27].…”

Section: H-bonding Evolutionsmentioning

confidence: 99%

Helix and H-bond formations of alanine-based peptides containing basic amino acids

et al. 2011

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We studied comprehensively the helicity and H-bonding evolutions during the folding processes of Lysand Arg-containing alanine-based peptides. The evolution of a-helical conformation concerning the entire sequence and each amino acid residue was examined, as well as the helix-forming propensities were characterized. The formation of various types of the intramolecular H-bonds was also investigated, pointing out the helix-stabilizing role of local interactions and the destabilizing role of non-local interplays. Our study led to the observation that the nonlocal H-bonds affected the evolution of helical conformations, as well as the entire folding processes.

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“…Also, various polyalanine systems have been extensively studied by using computational methods. [15][16][17][18][19][20][21][22][23][24][25] One of the most important polyalanines is the deca-alanine molecule, Ace-(Ala) 10 -NMe, [15][16][17][18][19][20][21][22][23] where Ace is the acetyl group (CH 3 CO) and NMe is the N-methyl amide (NHCH 3 ). Because the charges at the termini reduce the helix content, Ace and NMe are added to ensure the charge neutrality of the molecule and to protect its N-terminal and C-terminal.…”

Section: Introductionmentioning

confidence: 99%

Study of the Helical Protein Ace-(Ala)<SUB>10</SUB>-NMe in Solvent by Conformational Space Annealing

Kim¹

2013

Jnl of Comp & Theo Nano

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Using conformational space annealing (CSA), a powerful global optimization method, and the allatom CHARMM force field (param27) with the GB/SA continuum solvation potential, the energy landscape of the polyalanine Ace-(Ala) 10 -NMe in solvent (one of the standard models for the study of helix folding) is investigated. The native helical conformation is obtained for all 45 CSA runs. Gathering all conformations in the banks (final banks) of 45 independent CSA runs, we collect a total of 5588 (1045) distinct local minima, enabling us to investigate the energy landscape of Ace-(Ala) 10 -NMe in solvent. Our results show a funnel-shaped energy landscape leading to the native helical conformation. This kind of funnel-shaped landscape for Ace-(Ala) 10 -NMe in solvent is obtained for the first time.

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Direct computation of long time processes in peptides and proteins: Reaction path study of the coil‐to‐helix transition in polyalanine

Cited by 17 publications

References 33 publications

Observation of Two Families of Folding Pathways of BBL

Observation of Two Families of Folding Pathways of BBL

Helix and H-bond formations of alanine-based peptides containing basic amino acids

Study of the Helical Protein Ace-(Ala)<SUB>10</SUB>-NMe in Solvent by Conformational Space Annealing

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