Molecular Recognition Study on the Binding of Calcium to Calbindin D<sub>9k</sub> Based on 3D Reference Interaction Site Model Theory

Kiyota, Yasuomi; Takeda‐Shitaka, Mayuko

doi:10.1021/jp504822r

Cited by 10 publications

(13 citation statements)

References 44 publications

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“…1.8; Schrödinger, New York). Ca 2þ and Eu 3þ metal ion binding sites for the RYR1 domain were predicted by the integral-equation-based reference interaction site model (RISM) theory (48,49) using the rism1d and rism3d software implemented in the AMBER software package (ambermd.org) (50) and the PLACEVENT program (51) downloaded from the Placevent website (http://dansindhikara.com/ Software/Entries/2012/6/22_Placevent_New.html). The missing Eu 3þ parameters for RISM calculations were adopted from the article published by Li et al (52).…”

Section: In Silico Studiesmentioning

confidence: 99%

Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor

Sárközi

Komáromi

Jóna

et al. 2017

Biophysical Journal

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Ca regulates ryanodine receptor's (RyR) activity through an activating and an inhibiting Ca-binding site located on the cytoplasmic side of the RyR channel. Their altered sensitivity plays an important role in the pathology of malignant hyperthermia and heart failure. We used lanthanide ions (Ln) as probes to investigate the Ca sensors of RyR, because they specifically bind to Ca-binding proteins and they are impermeable to the channel. Eu's and Sm's action was tested on single RyR1 channels reconstituted into planar lipid bilayers. When the activating binding site was saturated by 50 μM Ca, Ln potently inhibited RyR's open probability (K Eu = 167 ± 5 nM and K Sm = 63 ± 3 nM), but in nominally 0 [Ca], low [Eu] activated the channel. These results suggest that Ln acts as an agonist of both Ca-binding sites. More importantly, the voltage-dependent characteristics of Ln's action led to the conclusion that the activating Ca binding site is located within the electrical field of the channel (in the vestibule). This idea was tested by applying the pore blocker toxin maurocalcine on the cytoplasmic side of RyR. These experiments showed that RyR lost reactivity to changing cytosolic [Ca] from 50 μM to 100 nM when the toxin occupied the vestibule. These results suggest that maurocalcine mechanically prevented Ca from dissociating from its binding site and support our vestibular Ca sensor-model further.

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Section: In Silico Studiesmentioning

confidence: 99%

Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor

Sárközi

Komáromi

Jóna

et al. 2017

Biophysical Journal

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“…33,34 Moreover, the barnase protein and ribose binding-protein have been successfully converted to an articial zymogen and a uorescent sensor for ribose, respectively, by applying the AFF modication. 24,36 However, theoretical investigations on the stable structures and conformational transitions of the AFF calbindin-D 9k protein have not yet been detailed so far. Because the AFF calbindin-D 9k protein is the modied switchable protein, the conformational transition of their N 0 and N conformations plays a key role in practising its switch function.…”

Section: Introductionmentioning

confidence: 99%

“…Theoretically, the cooperative interactions between the two binding sites of calcium ions in a WT calbindin-D 9k protein have been investigated using molecular dynamics simulations based on detailed atomic models. 24,36 However, theoretical investigations on the stable structures and conformational transitions of the AFF calbindin-D 9k protein have not yet been detailed so far. Therefore, it remains unclear what the dynamical transition mechanism of the two conformations is and what the exact allosteric communication in this transition is.…”

Section: Introductionmentioning

confidence: 99%

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D_9kprotein: a theoretical study

Tong

Wang

et al. 2015

RSC Adv.

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We carried out conventional molecular dynamics simulations, targeted molecular dynamics simulations and energy calculations for the two states (AFF-D 9k -N 0 and AFF-D 9k -N) of the alternate frame folding (AFF) calbindin-D 9k protein and their conformational transition in the Ca 2+ -free form to address the dynamical transition mechanism from AFF-D 9k -N 0 to AFF-D 9k -N states. We found that the structural characteristics of the two stable AFF-D 9k -N 0 and AFF-D 9k -N states present the coupled conformations of mutually exclusive folding. The transition from AFF-D 9k -N 0 to AFF-D 9k -N states may occur via two transition states and an intermediate with the first rate-controlling barrier of 4.7 kcal mol À1 and the second barrier of 1.7 kcal mol À1 . These results showed that the conformational transition pathway from AFF-D 9k -N 0 to AFF-D 9k -N is energetically feasible due to the low rate-controlling barrier. Moreover, the stabilities of the AFF-D 9k -N 0 and AFF-D 9k -N conformations calculated by the MM_PBSA method are consistent with the available experimental result. The transition mechanism involves the relative movements of the two mutually exclusive folding regions, EF2 and EF2 0 , and their coupled folding-unfolding. The crucial mediation of the deformation of EF1 hand located at the middle of the AFF calbindin-D 9k protein plays a key role in this transition process. The correlation analysis revealed the allosteric communications between the EF2 0 and EF2 regions via the mediation of the EF1 hand during the transition of AFF-D 9k -N 0 to AFF-D 9k -N. Fig. 6 The calculated residue B-factors of (a) AFF-D 9k -N (red) and (b) AFF-D 9k -N 0 (blue) in comparison with the experimental B-factors of the crystal calbindin-D 9k protein (black), respectively. The peaks with the number of residues at the loop regions are marked in grey.This journal is

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“…They applied the SDA method to the stability analysis of four small proteins (chignolin, CLN025, Trp-cage, and FSD-1) [158]. The SDA method was also applied to the analysis of ion-protein binding [159].…”

Section: Results Of Rmamentioning

confidence: 99%

Analysis of molecular dynamics simulations of 10-residue peptide, chignolin, using statistical mechanics: Relaxation mode analysis and three-dimensional reference interaction site model theory

2019

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Molecular dynamics simulation is a fruitful tool for investigating the structural stability, dynamics, and functions of biopolymers at an atomic level. In recent years, simulations can be performed on time scales of the order of milliseconds using specialpurpose systems. Since the most stable structure, as well as meta-stable structures and intermediate structures, is included in trajectories in long simulations, it is necessary to develop analysis methods for extracting them from trajectories of simulations. For these structures, methods for evaluating the stabilities, including the solvent effect, are also needed. We have developed relaxation mode analysis to investigate dynamics and kinetics of simulations based on statistical mechanics. We have also applied the three-dimensional reference interaction site model theory to investigate stabilities with solvent effects. In this paper, we review the results for designing amino-acid substitution of the 10-residue peptide, chignolin, to stabilize the misfolded structure using these developed analysis methods.It is important to develop analysis methods for molecular simulations of protein systems. We have developed relaxation mode analysis to investigate dynamics and kinetics of simulations. We also have applied the three-dimensional reference interaction site model theory to investigate stability with solvent effects. Here, we review the results for designing amino-acid substitution of 10-residue peptide, chignolin, to stabilize the misfolded structure using these analysis methods based on statistical mechanics. Background of mode decomposition methods for protein simulationsAs longer and larger MD simulations are performed, it has become increasingly important to develop methods to extract the "essential" information from the trajectory. The reduction in the large number of degrees of freedom of coordinates to a few collective ones is an active field of theo retical research. In NMA, the normal modes near the minimum potential energy of the protein molecule are obtained [3,24,25]. LMA investigates modes around a minimumenergy state, including the water effect [4,6,26,27]. An elastic network model and a Gaussian network model approximately calculate normal modes with large amplitudes by using the harmonic potential of coarse-grained models [28][29][30][31][32]. This method extracts collective modes with large amplitudes for large protein systems like viruses, because such proteins have rigid-like motions [33]. PCA, also called quasiharmonic analysis or the essential dynamics method [6,7,[34][35][36][37][38], is one of the most popular methods for analyzing the structural fluctuations around the average structure. The modes with large structure fluctuations are extracted and are considered cooperative movement, and the relation of these fluctuations with function has been widely examined. The obtained modes are also used as the axis of the free-energy surface. The JAM model was introduced for treating multiple-hierarchy free-energy landscapes [9]. They divided protei...

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Molecular Recognition Study on the Binding of Calcium to Calbindin D_9k Based on 3D Reference Interaction Site Model Theory

Cited by 10 publications

References 44 publications

Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor

Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D_9kprotein: a theoretical study

Analysis of molecular dynamics simulations of 10-residue peptide, chignolin, using statistical mechanics: Relaxation mode analysis and three-dimensional reference interaction site model theory

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Molecular Recognition Study on the Binding of Calcium to Calbindin D9k Based on 3D Reference Interaction Site Model Theory

Cited by 10 publications

References 44 publications

Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor

Lanthanides Report Calcium Sensor in the Vestibule of Ryanodine Receptor

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D9kprotein: a theoretical study

Analysis of molecular dynamics simulations of 10-residue peptide, chignolin, using statistical mechanics: Relaxation mode analysis and three-dimensional reference interaction site model theory

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Molecular Recognition Study on the Binding of Calcium to Calbindin D_9k Based on 3D Reference Interaction Site Model Theory

Structures and energies of the transition between two conformations of the alternate frame folding calbindin-D_9kprotein: a theoretical study