Sampling of near‐native protein conformations during protein structure refinement using a coarse‐grained model, normal modes, and molecular dynamics simulations

Stumpff-Kane, Andrew W.; Maksimiak, Katarzyna; Lee, Michael S.; Feig, Michael

doi:10.1002/prot.21674

Cited by 44 publications

(49 citation statements)

References 55 publications

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“…This feature is useful, for example, in refining computationally predicted structural models (43). In general, a modal analysis that can generate modes directly from a given structure offers a major advantage in conformational sampling.…”

Section: Discussionmentioning

confidence: 99%

A minimalist network model for coarse-grained normal mode analysis and its application to biomolecular x-ray crystallography

Ma²

2008

Proc. Natl. Acad. Sci. U.S.A.

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In this article, we report a method for coarse-grained normal mode analysis called the minimalist network model. The main features of the method are that it can deliver accurate low-frequency modes on structures without undergoing initial energy minimization and that it also retains the details of molecular interactions. The method does not require any additional adjustable parameters after coarse graining and is computationally very fast. Tests on modeling the experimentally measured anisotropic displacement parameters in biomolecular x-ray crystallography demonstrate that the method can consistently perform better than other commonly used methods including our own one. We expect this method to be effective for applications such as structural refinement and conformational sampling.all-atom normal modes ͉ elastic network model ͉ energy minimization ͉ normal mode analysis ͉ x-ray refinement N ormal mode analysis is a powerful tool for describing the global, collective, and functional motions of protein complexes (1-5). In this approach, the potential energy function of a protein is assumed to be harmonic so that protein motions can be described as a linear combination of a set of independent harmonic modes. Typically, only a few lowest-frequency modes with the largest amplitudes are sufficient to account for a majority of experimentally observed conformational fluctuations.Conventional normal mode analysis requires the calculation of an all-atom second-derivative matrix, the Hessian matrix, by using typical molecular mechanics force fields such as CHARMM (6-8) or AMBER (9-12). Thus, it requires substantial computer memory and processing power to perform the matrix diagonalization, which becomes a severe bottleneck in studies of supramolecular complexes. Moreover, to satisfy the harmonic approximation, the conventional method requires a lengthy initial energy-minimization step.To reduce the computational cost, many types of coarse-grained normal mode analyses have been developed (5,13,14). The most notable types include the rotations-translations of blocks (RTB) method (15) [also called block normal mode analysis (16)], allatom-derived coarse-grained methods (17, 18), and different variations of the elastic network model (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). The latter constructs the Hessian matrix from a highly simplistic Hamiltonian rather than a realistic molecular force field. Although elastic network models have been very successful, the quality of their modes is not optimal according to some recent studies, probably because of the usage of oversimplified Hamiltonians. In several reports that evaluated the use of low-frequency modes for interpreting crystallographic thermal parameters (28,30,31), the RTB approach with the CHARMM force field predicts anisotropic displacement parameters (ADPs) better than various elastic network models (28).Another limitation of the elastic network model is that it ignores molecular interaction details, which can be very important for certain cases (32). Also, in many a...

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Section: Discussionmentioning

confidence: 99%

A minimalist network model for coarse-grained normal mode analysis and its application to biomolecular x-ray crystallography

Ma²

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…This concern will be especially pertinent for proteins for which no structural information concerning their reaction pathway is available a priori to guide structural analysis. Nevertheless, we are confident that synergies can be developed between time-resolved wide-angle X-ray scattering studies and existing computational methods such as coarse grain models (Stumpff-Kane et al, 2008;Tozzini, 2005), normal-mode analysis of molecular dynamics trajectories (Stumpff-Kane et al, 2008) and geometric sampling of protein conformational transitions (Seeliger et al, 2007), so as to converge upon unique conformational states with a minimum number of additional structural assumptions. Moreover, variations of time-resolved wide-angle X-ray scattering which introduce heavy atoms or other strong scatterers into a protein (Andersson et al, 2008) could be used to develop objective methods for uniquely specifying structural changes, in analogy with the use of heavy-atom derivatives for phasing purposes in X-ray crystallography.…”

Section: Future Developments With Synchrotron Radiationmentioning

confidence: 99%

Time-resolved structural studies of protein reaction dynamics: a smorgasbord of X-ray approaches

et al. 2010

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Proteins undergo conformational changes during their biological function. As such, a high-resolution structure of a protein's resting conformation provides a starting point for elucidating its reaction mechanism, but provides no direct information concerning the protein's conformational dynamics. Several X-ray methods have been developed to elucidate those conformational changes that occur during a protein's reaction, including time-resolved Laue diffraction and intermediate trapping studies on three-dimensional protein crystals, and timeresolved wide-angle X-ray scattering and X-ray absorption studies on proteins in the solution phase. This review emphasizes the scope and limitations of these complementary experimental approaches when seeking to understand protein conformational dynamics. These methods are illustrated using a limited set of examples including myoglobin and haemoglobin in complex with carbon monoxide, the simple light-driven proton pump bacteriorhodopsin, and the superoxide scavenger superoxide reductase. In conclusion, likely future developments of these methods at synchrotron X-ray sources and the potential impact of emerging X-ray free-electron laser facilities are speculated upon.

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“…This is also supported by a hierarchical model of conformational substates since jumps between two energy basins do not involve changes equally throughout the whole structure, but only changes in few parts of the structure -such as closing and opening hinges in many enzymes. This finding can be also useful for developing structure refinement algorithms, 16,62 where only some parts of the chain are deformed and the core domain residues are kept fixed.…”

Section: Spearman Correlationmentioning

confidence: 97%

Elastic network normal modes provide a basis for protein structure refinement

Gniewek

Koliński

Jernigan

et al. 2012

The Journal of Chemical Physics

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It is well recognized that thermal motions of atoms in the protein native state, the fluctuations about the minimum of the global free energy, are well reproduced by the simple elastic network models (ENMs) such as the anisotropic network model (ANM). Elastic network models represent protein dynamics as vibrations of a network of nodes (usually represented by positions of the heavy atoms or by the C α atoms only for coarse-grained representations) in which the spatially close nodes are connected by harmonic springs. These models provide a reliable representation of the fluctuational dynamics of proteins and RNA, and explain various conformational changes in protein structures including those important for ligand binding. In the present paper, we study the problem of protein structure refinement by analyzing thermal motions of proteins in non-native states. We represent the conformational space close to the native state by a set of decoys generated by the I-TASSER protein structure prediction server utilizing template-free modeling. The protein substates are selected by hierarchical structure clustering. The main finding is that thermal motions for some substates, overlap significantly with the deformations necessary to reach the native state. Additionally, more mobile residues yield higher overlaps with the required deformations than do the less mobile ones. These findings suggest that structural refinement of poorly resolved protein models can be significantly enhanced by reduction of the conformational space to the motions imposed by the dominant normal modes.

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Sampling of near‐native protein conformations during protein structure refinement using a coarse‐grained model, normal modes, and molecular dynamics simulations

Cited by 44 publications

References 55 publications

A minimalist network model for coarse-grained normal mode analysis and its application to biomolecular x-ray crystallography

A minimalist network model for coarse-grained normal mode analysis and its application to biomolecular x-ray crystallography

Time-resolved structural studies of protein reaction dynamics: a smorgasbord of X-ray approaches

Elastic network normal modes provide a basis for protein structure refinement

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