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Title: The role of loop closure propensity in the refolding of Rop protein probed by molecular dynamics simulations
Authors: SHUKLA, RT
Keywords: Dimeric-Intermediate
Kinetic Model
Loop Closure
Protein Folding
Issue Date: 2013
Abstract: Rap protein is a homo-dimer of helix-turn-helix and has relatively slow folding and unfolding rates compared to other dimeric proteins of similar size. Fluorescence studies cited in literature suggest that mutation of turn residues D30-A31 to G30-G31 (Gly(2)) increases its folding and unfolding rates considerably. A further increase in number of glycines in the turn region results in decrease of folding rates compared to Gly(2) mutant. To understand the effect of glycine mutation on folding/unfolding rates of Rop and the conformational nature of turn region involved in formation of early folding species, we performed molecular dynamics simulations of turn peptides, (25)KLNELDADEQ(34) (DA peptide), (25)KLNELGGDEQ(34) (G(2) peptide), (25)KLNELGGGDEQ(33) (G(3) peptide) and (25)KLNELGGGEQ(34) (G(3)' peptide) from Rap at 300 K. Further Wt-Rop and mutant G(2)-Rop monomers and dimers were also studied separately by molecular dynamics simulations. Our results show that glycine based peptides (G(n) peptides) have a higher loop closure propensity compared to DA. Comparison of monomeric and dimeric Rop simulations suggests that dimeric Rap necessarily requires alpha(L) conformation to be sampled at D30/G30 position in the turn region. Since glycine (at position 30) can readily adopt alpha(L), conformation, G(n), loop plays a dual role in both facilitating loop closure as well as facilitating reorganization/packing of helices required for structural adjustment during dimer formation in the folding of Rap. Based on our simulation results and available literature, we suggest a tentative kinetic model for Rop folding which allows us to estimate the contribution of loop closure propensity to the overall folding rates. (C) 2013 Elsevier Inc. All rights reserved.
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