Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

Lee, In-Ho; Kim, Seung‐Yeon; Lee, Jooyoung

doi:10.1002/jcc.21288

Cited by 22 publications

(19 citation statements)

References 48 publications

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“…1, inset). This phenomenon has been observed in many folding simulation studies at similar timescales (3,8,10,32). In the 300 ns after the collapse, there was a large conformational adjustment during which the RMSD increased from <6 Å to >9 Å (Fig.…”

Section: Folding Eventsupporting

confidence: 72%

Folding Simulations of a De Novo Designed Protein with a βαβ Fold

Qi¹,

Huang²,

Liang

et al. 2010

Biophysical Journal

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betaalphabeta structural motifs are commonly used building blocks in protein structures containing parallel beta-sheets. However, to our knowledge, no stand-alone betaalphabeta structure has been observed in nature to date. Recently, for the first time that we know of, a small protein with an independent betaalphabeta structure (DS119) was successfully designed in our laboratory. To understand the folding mechanism of DS119, in the study described here, we carried out all-atom molecular dynamics and coarse-grained simulations to investigate its folding pathways and energy landscape. From all-atom simulations, we successfully observed the folding event and got a stable folded structure with a minimal root mean-square deviation of 2.6 A with respect to the NMR structure. The folding process can be described as a fast collapse phase followed by rapid formation of the central helix, and then slow formation of a parallel beta-sheet. By using a native-centric Gō-like model, the cooperativity of the system was characterized in terms of the calorimetric criterion, sigmoidal transitions, conformation distribution shifts, and free-energy profiles. DS119 was found to be an incipient downhill folder that folds more cooperatively than a downhill folder, but less cooperatively than a two-state folder. This may reflect the balance between the two structural elements of DS119: the rapidly formed alpha-helix and the slowly formed parallel beta-sheet. Folding times estimated from both the all-atom simulations and the coarse-grained model were at microsecond level, making DS119 another fast folder. Compared to fast folders reported previously, DS119 is, to the best of our knowledge, the first that exhibits a parallel beta-sheet.

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Section: Folding Eventsupporting

confidence: 72%

Folding Simulations of a De Novo Designed Protein with a βαβ Fold

Qi¹,

Huang²,

Liang

et al. 2010

Biophysical Journal

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“…The folding of the villin headpiece helical subdomain (HP36) has extensively been studied both experimentally and computationally . Two papers from the Raleigh group showed using both CD and NMR spectroscopy that HP21, a mostly disordered 21‐residue peptide fragment derived from HP36, maintains a native‐like structure in the unfolded state.…”

Section: Introductionmentioning

confidence: 99%

“…The folding of the villin headpiece helical subdomain (HP36) has extensively been studied both experimentally [18][19][20][21][22][23][24][25][26][27][28][29][30][31] and computationally. [32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Two papers from the Raleigh group 48,49 showed using both CD and NMR spectroscopy that HP21, a mostly disordered 21-residue peptide fragment derived from HP36, maintains a native-like structure in the unfolded state. The structure and sequence of HP36 with the portion corresponding to HP21 highlighted are shown in Figure 1.…”

Section: Introductionmentioning

confidence: 99%

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

Baltzis

Glykos

2015

Protein Science

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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.

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“…When the ADMD method was applied to study the folding pathway of 36-residue villin headpiece subdomain HP-36 [ 19 ], we found that the folding was initiated by hydrophobic collapse, after which concurrent formation of full tertiary structure and α -helical secondary structure was observed. The C-terminal helix was observed to form first, followed by the N-terminal helix positioned in its native orientation.…”

Section: Introductionmentioning

confidence: 99%

A Folding Pathway Model of Mini-Protein BBA5

Kim

Lee

2015

BioMed Research International

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We present the folding pathway model of mini-protein BBA5, a bundle of secondary structures, α-helix and β-hairpin, by using action-derived molecular dynamics (ADMD) simulations. From ten independent ADMD simulations, we extracted common features of the folding pathway of BBA5, from which we found that the early stage chain compaction was followed by the formation of C-terminal α-helix. The N-terminal β-hairpin was observed to form only after α-helix was stabilized. This result is in good agreement with the experimental observation that BBA5 mutants were moderately cooperative folders, and their C-terminal helical fragments were of higher secondary structure propensity while the N-terminal hairpin fragments were of a random coil spectrum. We found that the most flexible part of BBA5 is the N-terminal four residues. Although both are made of the identical ββα motif, the secondary structure formation sequence of BBA5 is found to be different from that of FSD-1. Finally, a description of the folding pathway in terms of principal component analysis is presented to characterize the folding dynamics in reduced dimensions. With only three principal components, we were able to describe 83.4% of the pathway.

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Dynamic folding pathway models of the villin headpiece subdomain (HP‐36) structure

Cited by 22 publications

References 48 publications

Folding Simulations of a De Novo Designed Protein with a βαβ Fold

Folding Simulations of a De Novo Designed Protein with a βαβ Fold

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

A Folding Pathway Model of Mini-Protein BBA5

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