Dataset Information

Conformational free-energy landscapes for a peptide in saline environments.

ABSTRACT: The conformations that proteins adopt in solution are a function of both their primary structure and surrounding aqueous environment. Recent experimental and computational work on small peptides, e.g., polyK, polyE, and polyR, have highlighted an interesting and unusual behavior in the presence of aqueous ions such as ClO??, Na?, and K?. Notwithstanding the aforementioned studies, as of this writing, the nature of the driving force induced by the presence of ions and its role on the conformational stability of peptides remains only partially understood. Molecular-dynamics simulations have been performed on the heptapeptide AEAAAEA in NaCl and KCl solutions at concentrations of 0.5, 1.0, and 2.0 M. Metadynamics in conjunction with a three-dimensional model reaction coordinate was used to sample the conformational space of the peptide. All simulations were run for 2 ?s. Free-energy landscapes were computed over the model reaction coordinate for the peptide in each saline assay as well as in the absence of ions. Circular dichroism spectra were also calculated from each trajectory. In the presence of Na? and K? ions, no increase in helicity is observed with respect to the conformation in pure water.

SUBMITTER: Gaborek TJ

PROVIDER: S-EPMC3525846 | biostudies-other | 2012 Dec

REPOSITORIES: biostudies-other

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Conformational free-energy landscapes for a peptide in saline environments.

Gaborek Timothy J TJ Chipot Christophe C Madura Jeffry D JD

Biophysical journal 20121218 12

The conformations that proteins adopt in solution are a function of both their primary structure and surrounding aqueous environment. Recent experimental and computational work on small peptides, e.g., polyK, polyE, and polyR, have highlighted an interesting and unusual behavior in the presence of aqueous ions such as ClO₄⁻, Na⁺, and K⁺. Notwithstanding the aforementioned studies, as of this writing, the nature of the driving force induced by the presence of ions and its role on the conformation ...[more]

PMID: 23260053

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Project description:Membrane reorientation of oncogenic RAS proteins is emerging as an important modulator of their functions. Previous studies have shown that the most common orientations include those with either the three C-terminal α-helices (OS1) or N-terminal β-strands (OS2) of the catalytic domain facing the membrane. OS1 and OS2 differ by the degree to which the effector-interacting surface is occluded by the membrane. However, the relative stability of these states and the rates of transition between them remained undetermined. How mutations might modulate preferences for specific orientation states is also far from clear. The current work attempted to address these questions through a comprehensive analysis of two 20 μs-long atomistic molecular dynamics simulations. The simulations were conducted on the oncogenic G12D and Q61H KRAS mutants bound to an anionic lipid bilayer. G12D and Q61H are among the most prevalent cancer-causing mutations at the P-loop and switch 2 regions of KRAS, respectively. We found that both mutants fluctuate in a similar manner between OS1 and OS2 via an intermediate orientation OS0, and both favor the signaling competent OS1 and OS0 over the occluded OS2. However, they differ in the details, such as in the extent to which they sample OS1. Analysis of the orientation free-energy landscapes estimated from the simulations indicate that OS1 and OS2 are the most stable states. However, the overall free energy surface is rugged, indicating a large diversity of conformations including at least two substates in each orientation state that differ in stability only by about 0.5-1.0 kcal/mol. Reversible transitions between OS1 and OS2 occur via two well-defined pathways that traverse OS0. In the minimum energy path, helix 4 remains close to the membrane as the angle of the catalytic domain from the membrane plane changes, resulting in a barrier of ∼1 kcal/mol for OS1/OS2 interconversions. Estimation of the rates of the various transitions based on survival probabilities yielded two rate constants in the order of 107 and 106 s-1, which we attribute to intrinsic protein conformational dynamics and transient protein-lipid interactions, respectively. The faster process dominates every transition, confirming a previous suggestion that RAS membrane reorientation is driven by conformational fluctuations rather than protein-lipid interactions.

Dataset Information

Conformational free-energy landscapes for a peptide in saline environments.

Publications

Conformational free-energy landscapes for a peptide in saline environments.

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