New Advances in Normal Mode Analysis of Supermolecular Complexes and Applications to Structural Refinement

Ma, Jianpeng

doi:10.2174/1389203043486892

Cited by 68 publications

(76 citation statements)

References 52 publications

(73 reference statements)

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“…Normal mode analysis (NMA) is a method for characterizing the motions of macromolecules based on basis vectors (normal modes), which describes the flexibility of the molecule (83)(84)(85). The visual inspection of the 20 lowest-frequency normal modes computed by the elNémo server showed that the first four lowest frequencies of the normal mode of vibrations corresponded to the largest-amplitude motions of the extended and collapsed conformations of the AniA structure (86,87).…”

Section: Methodsmentioning

confidence: 99%

Peptide Inhibitors Targeting the Neisseria gonorrhoeae Pivotal Anaerobic Respiration Factor AniA

Sikora

Mills

Weber

et al. 2017

Antimicrob Agents Chemother

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Neisseria gonorrhoeae causes the sexually transmitted infection gonorrhea, which is highly prevalent worldwide and has a major impact on reproductive and neonatal health. The superbug status of N. gonorrhoeae necessitates the development of drugs with different mechanisms of action. Here, we focused on targeting the nitrite reductase AniA, which is a pivotal component of N. gonorrhoeae anaerobic respiration and biofilm formation. Our studies showed that gonococci expressing AniA containing the altered catalytic residues D137A and H280A failed to grow under anaerobic conditions, demonstrating that the nitrite reductase function is essential. To facilitate the pharmacological targeting of AniA, new crystal structures of AniA were refined to 1.90-Å and 2.35-Å resolutions, and a phage display approach with libraries expressing randomized linear dodecameric peptides or heptameric peptides flanked by a pair of cysteine residues was utilized. Biopanning experiments led to the identification of 29 unique peptides, with 1 of them, C7-3, being identified multiple times. Evaluation of their ability to interact with AniA using enzyme-linked immunosorbent assay and computational docking studies revealed that C7-3 was the most promising inhibitor, binding near the type 2 copper site of the enzyme, which is responsible for interaction with nitrite. Subsequent enzymatic assays and biolayer interferometry with a synthetic C7-3 and its derivatives, C7-3m1 and C7-3m2, demonstrated potent inhibition of AniA. Finally, the MIC 50 value of C7-3 and C7-3m2 against anaerobically grown N. gonorrhoeae was 0.6 mM. We present the first peptide inhibitors of AniA, an enzyme that should be further exploited for antigonococcal drug development.

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Section: Methodsmentioning

confidence: 99%

Peptide Inhibitors Targeting the Neisseria gonorrhoeae Pivotal Anaerobic Respiration Factor AniA

Sikora

Mills

Weber

et al. 2017

Antimicrob Agents Chemother

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“…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).…”

mentioning

confidence: 99%

“…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).…”

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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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“…In the elastic network model (ENM) a protein structure is represented by a linear elastic network (EN) in which each node is the Cα atom of a residue and the all-atoms molecular mechanics force-field is replaced by a ball and spring harmonic (Hookean) potential, combined with a coarse grained (CG) representation of the protein. There are various ENM model types of coarse-grained normal mode analyses [2,21,22]. Among these models, anisotropic normal mode model (ANM) is a simple physics-based model that use the 3N mass-weighted coordinates of the nodes as generalized coordinates, which exclusively depends on inter-residue contact topology that can be described by a matrix version of Newton's second law of motion (quadratic potential) with a uniform force constant for all atomic interactions within a cutoff distance reproduced almost identically the low-frequency modes of motion obtained with a detailed force field [23,24].…”

Section: Introductionmentioning

confidence: 99%

Dynamics of βB2-Crystallin Motion Based on Principal Component Analysis and Normal Mode Analysis

Gawad¹

2015

CBB

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Abstract:The primary function of lens is to focus images perfectly on the retina. Lens crystallins however are flexible nanomachines that frequently accomplish their biological function by collective atomic motions in and/or out the lens. Although genetic and biochemical data on the βB2-crystallin protein are available from several sources, the correlation between conformational changes and dynamic behavior at the atomic level remains to be understood. The βB2-crystallin dimer has studied through a combination of molecular dynamics simulations, principal component analysis (PCA) and normal mode analyses. The changes in interface buried surface shows the mutual orientation of individual domains in βB2-crystallin dimer. The dominant PCA modes for concerted motions of the protein atoms were monitored in a lower-dimensions subspace. Three types of movements found in βB2-crystallin dimer, which are a twist propeller motion, a scissors type hinge motion, and a shear motion between the domains. Both the RMSF and the normal-mode dynamics showed that N-terminal β-sheet is the most correlated segments.

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New Advances in Normal Mode Analysis of Supermolecular Complexes and Applications to Structural Refinement

Cited by 68 publications

References 52 publications

Peptide Inhibitors Targeting the Neisseria gonorrhoeae Pivotal Anaerobic Respiration Factor AniA

Peptide Inhibitors Targeting the Neisseria gonorrhoeae Pivotal Anaerobic Respiration Factor AniA

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

Dynamics of βB2-Crystallin Motion Based on Principal Component Analysis and Normal Mode Analysis

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