Early events in the folding of an amphipathic peptide: A multinanosecond molecular dynamics study

Chipot, Christophe; Maigret, Bernard; Pohorille, Andrew

doi:10.1002/(sici)1097-0134(19990901)36:4<383::aid-prot2>3.0.co;2-p

Cited by 24 publications

(16 citation statements)

References 115 publications

(107 reference statements)

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“…Complicated interfacial environments such as lipid bilayers present great obstacles to complete sampling of peptide conformations in MD simulations [47,48]. In this sense, it is not surprising that the helical starting conformations remain stable over the timescale of our simulations.…”

Section: Discussionmentioning

confidence: 95%

Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin S3 with lipid bilayers: molecular-dynamics simulations

Shepherd

Vogel

Tieleman

2003

Biochemical Journal

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Molecular-dynamics simulations covering 30 ns of both a natural and a synthetic antimicrobial peptide in the presence of a zwitterionic lipid bilayer were performed. In both simulations, copies of the peptides were placed in an alpha-helical conformation on either side of the bilayer about 10 A (1 A=0.1 nm) from the interface, with either the hydrophobic or the positively charged face of the helix directed toward the bilayer surface. The degree of peptide-lipid interaction was dependent on the starting configuration: surface binding and subsequent penetration of the bilayer was observed for the hydrophobically oriented peptides, while the charge-oriented peptides demonstrated at most partial surface binding. Aromatic residues near the N-termini of the peptides appear to play an important role in driving peptide-lipid interactions. A correlation between the extent of peptide-lipid interactions and helical stability was observed in the simulations. Insertion of the peptides into the bilayer caused a dramatic increase in the lateral area per lipid and decrease in the bilayer thickness, resulting in substantial disordering of the lipid chains. Results from the simulations are consistent with early stages of proposed mechanisms for the lytic activity of antimicrobial peptides. In addition to these 'free' simulations, 25 ns simulations were carried out with the peptides constrained at three different distances relative to the bilayer interface. The constraint forces are in agreement with the extent of peptide-bilayer insertion observed in the free simulations.

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Section: Discussionmentioning

confidence: 95%

Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin S3 with lipid bilayers: molecular-dynamics simulations

Shepherd

Vogel

Tieleman

2003

Biochemical Journal

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“…In a previous computational study of interfacial folding involving an undecamer peptide consisting of a sequence of Leu and Gln residues capable of forming an amphipathic ␣-helix, it was shown that if the peptide was placed on the water side in a nonamphipathic ␤-sheet conformation, the peptide would still migrate to the water/hexane interface and adopt a nonhelical amphipathic conformation with nearly optimal amphipathy (Chipot et al, 1999). Almost no nonamphipathic conformations were observed at the interface.…”

Section: Discussionmentioning

confidence: 99%

“…Although the partitioning of residues into one of the phases can initiate secondary structure formation, transitions between different amphipathic structures at an interface could require the surmounting of high free energy barriers. Nonoptimized folded structures with a satisfactory partitioning of the residues may represent local minimum on the free energy surface and impede folding (Chipot et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Study of the Folding of Hydrophobin SC3 at a Hydrophilic/Hydrophobic Interface

Zangi

Vocht

Robillard

et al. 2002

Biophysical Journal

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Hydrophobins are fungal proteins that self-assemble at hydrophilic/hydrophobic interfaces into amphipathic membranes. These assemblages are extremely stable and posses the remarkable ability to invert the polarity of the surface on which they are adsorbed. Neither the three-dimensional structure of a hydrophobin nor the mechanism by which they function is known. Nevertheless, there are experimental indications that the self-assembled form of the hydrophobins SC3 and EAS at a water/air interface is rich with ␤-sheet secondary structure. In this paper we report results from molecular dynamics simulations, showing that fully extended SC3 undergoes fast (ϳ100 ns) folding at a water/hexane interface to an elongated planar structure with extensive ␤-sheet secondary elements. Simulations in each of the bulk solvents result in a mainly unstructured globular protein. The dramatic enhancement in secondary structure, whether kinetic or thermodynamic in origin, highlights the role interfaces between phases with large differences in polarity can have on folding. The partitioning of the residue side-chains to one of the two phases can serve as a strong driving force to initiate secondary structure formation. The interactions of the side-chains with the environment at an interface can also stabilize configurations that otherwise would not occur in a homogenous solution.

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“…The explosion of computing capacity enabled us to simulate folding of peptides or small proteins in explicit solvent (71). Daura et al (70,72,73) were able to fold and unfold a b-heptapeptide in methanol, Chipot et al to fold some helical peptides at a water/hexane interface (74,75). In 1998, Duan and Kollman brought a milestone in explicit simulations by describing an early folding event of a small protein (the villin headpiece) in a microsecond molecular dynamics (76).…”

Section: Introductionmentioning

confidence: 99%

Kinetics and Thermodynamics of Type VIII β-Turn Formation: A CD, NMR, and Microsecond Explicit Molecular Dynamics Study of the GDNP Tetrapeptide

Fuchs

Bonvin

Bochicchio

et al. 2006

Biophysical Journal

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We report an experimental and theoretical study on type VIII beta-turn using a designed peptide of sequence GDNP. CD and NMR studies reveal that this peptide exists in equilibrium between type VIII beta-turn and extended conformations. Extensive MD simulations give a description of the free energy landscape of the peptide in which we retrieve the same two main conformations suggested by the experiments. The free energy difference between the two conformational states is very small and the transition between them occurs within a few kT at 300 K on a nanosecond timescale. The equilibrium is mainly driven by entropic contribution, which favors extended conformations over beta-turns. This confirms other theoretical studies showing that beta-turns are marginally stable in water solution because of the larger entropy of the extended state unless some stabilizing interactions exist. Our observations may be extended to any type of beta-turn and have important consequences for protein folding. A comparison of our MD and CD results also suggests a possible type VIII beta-turn CD signature indicated by one main band at 200 nm, close to that of random coil, and a fairly large shoulder at 220 nm. Last, our results clearly show that the XXXP motif can only fold into a type VIII beta-turn, which is consistent with its fairly strong propensity for this type of turn. This important finding may help for peptide design and is in line with recent studies on bioactive elastin peptides.

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Early events in the folding of an amphipathic peptide: A multinanosecond molecular dynamics study

Abstract: Folding of the capped LQQLLQQLLQL

Cited by 24 publications

References 115 publications

Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin S3 with lipid bilayers: molecular-dynamics simulations

Interactions of the designed antimicrobial peptide MB21 and truncated dermaseptin S3 with lipid bilayers: molecular-dynamics simulations

Molecular Dynamics Study of the Folding of Hydrophobin SC3 at a Hydrophilic/Hydrophobic Interface

Kinetics and Thermodynamics of Type VIII β-Turn Formation: A CD, NMR, and Microsecond Explicit Molecular Dynamics Study of the GDNP Tetrapeptide

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