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Protein dynamics investigated by inherent structure analysis.

ABSTRACT: Molecular dynamics (MD) simulations provide essential information about the thermodynamics and dynamics of proteins. To construct the free-energy surface from equilibrium trajectories, it is necessary to group the individual snapshots in a meaningful way. The inherent structures (IS) are shown to provide an appropriate discretization of the trajectory and to avoid problems that can arise in clustering algorithms that have been employed previously. The IS-based approach is illustrated with a 30-ns room temperature "native" state MD simulation of a 10-residue peptide in a beta-hairpin conformation. The transitions between the IS are used to construct a configuration space network from which a one-dimensional free-energy profile is obtained with the mincut method. The results demonstrate that the IS approach is useful and that even for this simple system, there exists a nontrivial organization of the native state into several valleys separated by barriers as high as 3 kcal/mol. Further, by introducing a coarse-grained network, it is demonstrated that there are multiple pathways connecting the valleys. This scenario is hidden when the snapshots of the trajectory are used directly with rmsd clustering to compute the free-energy profile. Application of the IS approach to the native state of the PDZ2 signaling domain indicates its utility for the study of biologically relevant systems.

SUBMITTER: Rao F

PROVIDER: S-EPMC2889081 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Protein dynamics investigated by inherent structure analysis.

Rao Francesco F Karplus Martin M

Proceedings of the National Academy of Sciences of the United States of America 20100430 20

Molecular dynamics (MD) simulations provide essential information about the thermodynamics and dynamics of proteins. To construct the free-energy surface from equilibrium trajectories, it is necessary to group the individual snapshots in a meaningful way. The inherent structures (IS) are shown to provide an appropriate discretization of the trajectory and to avoid problems that can arise in clustering algorithms that have been employed previously. The IS-based approach is illustrated with a 30-n ...[more]

PMID: 20435910

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Project description:We have studied the structure of (Ala)5, a model unfolded peptide, using a combination of 2D IR spectroscopy and molecular dynamics (MD) simulation. Two different isotopomers, each bis-labeled with (13)C?O and (13)C?(18)O, were strategically designed to shift individual site frequencies and uncouple neighboring amide-I' modes. 2D IR spectra taken under the double-crossed ??/4, -?/4, Y, Z? polarization show that the labeled four-oscillator systems can be approximated by three two-oscillator systems. By utilizing the different polarization dependence of diagonal and cross peaks, we extracted the coupling constants and angles between three pairs of amide-I' transition dipoles through spectral fitting. These parameters were related to the peptide backbone dihedral angles through DFT calculated maps. The derived dihedral angles are all located in the polyproline-II (ppII) region of the Ramachandran plot. These results were compared to the conformations sampled by Hamiltonian replica-exchange MD simulations with three different CHARMM force fields. The C36 force field predicted that ppII is the dominant conformation, consistent with the experimental findings, whereas C22/CMAP predicted similar population for ?+, ?, and ppII, and the polarizable Drude-2013 predicted dominating ? structure. Spectral simulation based on MD representative conformations and structure ensembles demonstrated the need to include multiple 2D spectral features, especially the cross-peak intensity ratio and shape, in structure determination. Using 2D reference spectra defined by the C36 structure ensemble, the best spectral simulation is achieved with nearly 100% ppII population, although the agreement with the experimental cross-peak intensity ratio is still insufficient. The dependence of population determination on the choice of reference structures/spectra and the current limitations on theoretical modeling relating peptide structures to spectral parameters are discussed. Compared with the previous results on alanine based oligopeptides, the dihedral angles of our fitted structure, and the most populated ppII structure from the C36 simulation are in good agreement with those suggesting a major ppII population. Our results provide further support for the importance of ppII conformation in the ensemble of unfolded peptides.

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Protein dynamics investigated by inherent structure analysis.

Publications

Protein dynamics investigated by inherent structure analysis.

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