scholarly journals Molecular Dynamics Simulations of Wild Type and Mutants of SAPAP in Complexed with Shank3

2019 ◽  
Vol 20 (1) ◽  
pp. 224 ◽  
Author(s):  
Lianhua Piao ◽  
Zhou Chen ◽  
Qiuye Li ◽  
Ranran Liu ◽  
Wei Song ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Specific Binding ◽  
Neurological Diseases ◽  
Pdz Domain ◽  
Dynamics Simulation ◽  
Binding Motif ◽  
Wild Type ◽  
Set Up ◽  
Dynamics Simulations ◽  
High Flexibility

Specific interactions between scaffold protein SH3 and multiple ankyrin repeat domains protein 3 (Shank3) and synapse-associated protein 90/postsynaptic density-95–associated protein (SAPAP) are essential for excitatory synapse development and plasticity. In a bunch of human neurological diseases, mutations on Shank3 or SAPAP are detected. To investigate the dynamical and thermodynamic properties of the specific binding between the N-terminal extended PDZ (Post-synaptic density-95/Discs large/Zonaoccludens-1) domain (N-PDZ) of Shank3 and the extended PDZ binding motif (E-PBM) of SAPAP, molecular dynamics simulation approaches were used to study the complex of N-PDZ with wild type and mutated E-PBM peptides. To compare with the experimental data, 974QTRL977 and 966IEIYI970 of E-PBM peptide were mutated to prolines to obtain the M4P and M5P system, respectively. Conformational analysis shows that the canonical PDZ domain is stable while the βN extension presents high flexibility in all systems, especially for M5P. The high flexibility of βN extension seems to set up a barrier for the non-specific binding in this area and provide the basis for specific molecular recognition between Shank3 and SAPAP. The wild type E-PBM tightly binds to N-PDZ during the simulation while loss of binding is observed in different segments of the mutated E-PBM peptides. Energy decomposition and hydrogen bonds analysis show that M4P mutations only disrupt the interactions with canonical PDZ domain, but the interactions with βN1′ remain. In M5P system, although the interactions with βN1′ are abolished, the binding between peptide and the canonical PDZ domain is not affected. The results indicate that the interactions in the two-binding site, the canonical PDZ domain and the βN1′ extension, contribute to the binding between E-PBM and N-PDZ independently. The binding free energies calculated by MM/GBSA (Molecular Mechanics/Generalized Born Surface Area) are in agreement with the experimental binding affinities. Most of the residues on E-PBM contribute considerably favorable energies to the binding except A963 and D964 in the N-terminal. The study provides information to understand the molecular basis of specific binding between Shank3 and SAPAP, as well as clues for design of peptide inhibitors.

scholarly journals The Impact of Mutation L138F/L210F on the Orai Channel: A Molecular Dynamics Simulation Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoqian Zhang ◽  
Hua Yu ◽  
Xiangdong Liu ◽  
Chen Song
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Calcium Release ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Wild Type ◽  
Hydrophobic Region ◽  
In The Wild ◽  
Dynamics Simulations ◽  
The Impact

The calcium release-activated calcium channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the wild-type. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously unobserved feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.

scholarly journals The effect of the multiple mutations in Omicron RBD on its binding to human ACE2 receptor and immune evasion: an investigation of molecular dynamics simulations

2021 ◽  
Author(s):  
Leyun Wu ◽  
Liping Zhou ◽  
Mengxia Mo ◽  
Yishui Li ◽  
Jiaxin Han ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Receptor Binding ◽  
Immune Evasion ◽  
Binding Motif ◽  
Binding Affinities ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
Dynamics Simulations

SARS-coronavirus-2 (SARS-CoV2) Omicron variant (B.1.1.529) is of great concern to the world due to multiple mutations that may have an impact on transmissibility and immune evasion. Compared to the wild type (WT), there are 15 mutations in the Omicron receptor-binding domain (RBD), 10 of which are in the receptor-binding motif (RBM), where the host angiotensin-converting enzyme 2 (ACE2) interacts directly with. As a comparison, the currently dominant variant Delta (B.1.617.2) only has 2 mutations (L452R and T478K) or an additional E484K mutation in the RBM. As many as 15 mutations in Omicron RBD make it very hard to predict whether the mutations would increase the binding affinity to ACE2, particularly considering that 10 mutations crowded in the RBM. To understand the combinatorial mutation effect on Omicron RBD binding to ACE2 and potential immune evasion, we calculated the binding affinities of the WT/Delta/Omicron RBDs to ACE2 and antibodies with 600 ns molecular dynamics simulations for each system. We found that Omicron RBD has slightly weaker ACE2 affinities than WT RBD (-29.39 ± 2.96 Kcal/mol vs. -33.13 ± 3.26 Kcal/mol), and much lower affinities than Delta RBD (-42.76 ± 2.38 Kcal/mol). Further analysis revealed that Omicron N501Y increase ACE2 binding but Q493K and Q498R decrease ACE2 binding. In addition, Omicron RBD might escape the launched monoclonal antibodies (mAbs) Etesevimab and clinical BD-368-2 but may still sensitive to the launched mAbs Bebtelovimab.

scholarly journals AMPA GluA2 subunit competitive inhibitors for PICK1 PDZ domain: Pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation, and ADME studies

2021 ◽  
Author(s):  
Shravan B. Rathod ◽  
Pravin B. Prajapati ◽  
Ranjan Pal ◽  
Mohmedyasin F. Mansuri
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Synaptic Plasticity ◽  
Molecular Dynamics Simulation ◽  
Virtual Screening ◽  
Neurological Diseases ◽  
Pdz Domain ◽  
Dynamics Simulation ◽  
Scaffolding Protein ◽  
Beneficial Effects

PICK1 (Protein interacting with C kinase-1) plays a key role in the regulation of intracellular trafficking of AMPA GluA2 subunit that is linked with synaptic plasticity. PICK1 is a scaffolding protein and binds numerous proteins through its PDZ domain. Research showed that synaptic plasticity is altered upon disrupting the GluA2-PDZ interactions. Inhibiting PDZ and GluA2 binding lead to beneficial effects in the cure of neurological diseases thus, targeting PDZ domain is proposed as a novel therapeutic target in such diseases. For this, various classes of synthetic peptides were tested. Though small organic molecules have been utilized to prevent these interactions, the number of such molecules is inadequate. Hence, in this study, ten molecular libraries containing large number of molecules were screened against the PDZ domain using pharmacophore-based virtual screening to find the best hits for the PDZ domain. Molecular docking and molecular dynamics simulation studies revealed that Hit_II is a potent inhibitor for the PDZ domain and confirm the allosteric nature of Hit_III. Additionally, ADME analysis suggests the drug-likeness of both Hit_II and Hit_III. This study suggests that tested hits may have potency against the PDZ domain and can be considered effective to treat neurological disorders.

Multicanonical Molecular Dynamics Simulation Study of the Liquid-Solid and Solid-Solid Transitions in Lennard-Jones Clusters

2011 ◽  
Author(s):  
Toshihiro Kaneko ◽  
Kenji Yasuoka ◽  
Ayori Mitsutake ◽  
Xiao Cheng Zeng
Keyword(s):  
Molecular Dynamics ◽  
Heat Capacity ◽  
Transition Temperature ◽  
Peak Position ◽  
Temperature Curve ◽  
Dynamics Simulation ◽  
Lennard Jones ◽  
Dynamics Simulations ◽  
First Time ◽  
Good Agreement

Multicanonical molecular dynamics simulations are applied, for the first time, to study the liquid-solid and solid-solid transitions in Lennard-Jones (LJ) clusters. The transition temperatures are estimated based on the peak position in the heat capacity versus temperature curve. For LJ31, LJ58 and LJ98, our results on the solid-solid transition temperature are in good agreement with previous ones. For LJ309, the predicted liquid-solid transition temperature is also in agreement with previous result.

scholarly journals Reactive molecular dynamics simulation of the high-temperature pyrolysis of 2,2′,2′′,4,4′,4′′,6,6′,6′′-nonanitro-1,1′:3′,1′′-terphenyl (NONA)

RSC Advances ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 5507-5515
Author(s):  
Liang Song ◽  
Feng-Qi Zhao ◽  
Si-Yu Xu ◽  
Xue-Hai Ju
Keyword(s):  
Molecular Dynamics ◽  
High Temperature ◽  
Molecular Dynamics Simulation ◽  
Molecular Dynamics Simulations ◽  
Dynamics Simulation ◽  
Reactive Molecular Dynamics ◽  
Ring Compounds ◽  
Fused Ring ◽  
Dynamics Simulations

The bimolecular and fused ring compounds are found in the high-temperature pyrolysis of NONA using ReaxFF molecular dynamics simulations.

scholarly journals Exploration of the cofactor specificity of wild-type phosphite dehydrogenase and its mutant using molecular dynamics simulations

RSC Advances ◽  
2021 ◽  
Vol 11 (24) ◽  
pp. 14527-14533
Author(s):  
Kunlu Liu ◽  
Min Wang ◽  
Yubo Zhou ◽  
Hongxiang Wang ◽  
Yudong Liu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Wild Type ◽  
Cofactor Specificity ◽  
Phosphite Dehydrogenase ◽  
Dynamics Simulations

Phosphite dehydrogenase (Pdh) catalyzes the NAD-dependent oxidation of phosphite to phosphate with the formation of NADH.

Observation of “Ionic Lock” Formation in Molecular Dynamics Simulations of Wild-Type β1and β2Adrenergic Receptors

Biochemistry ◽  
2009 ◽  
Vol 48 (22) ◽  
pp. 4789-4797 ◽  
Author(s):  
Stefano Vanni ◽  
Marilisa Neri ◽  
Ivano Tavernelli ◽  
Ursula Rothlisberger
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Wild Type ◽  
Dynamics Simulations

Molecular Dynamics Simulation Study of Lecithin Inhibiting Hydrate-Dissociation

2017 ◽  
Vol 890 ◽  
pp. 252-259
Author(s):  
Le Wang ◽  
Guan Cheng Jiang ◽  
Xin Lin ◽  
Xian Min Zhang ◽  
Qi Hui Jiang
Keyword(s):  
Molecular Dynamics ◽  
Water Movement ◽  
Simulation Analysis ◽  
Mass Density ◽  
Dynamics Simulation ◽  
Dissociation Process ◽  
Hydrate Dissociation ◽  
Hydrocarbon Chains ◽  
Dynamics Simulations ◽  
Mass Density Profile

Molecular dynamics simulations are used to study the dissociation inhibiting mechanism of lecithin for structure I hydrates. Adsorption characteristics of lecithin and PVP (poly (N-vinylpyrrolidine)) on the hydrate surfaces were performed in the NVT ensemble at temperatures of 277K and the hydrate dissociation process were simulated in the NPT ensemble at same temperature. The results show that hydrate surfaces with lecithin is more stable than the ones with PVP for the lower potential energy. The conformation of lecithin changes constantly after the balanced state is reached while the PVP molecular dose not. Lecithin molecule has interaction with lecithin nearby and hydrocarbon-chains of lecithin molecules will form a network to prevent the diffusion of water and methane molecules, which will narrow the available space for hydrate methane and water movement. Compared with PVP-hydrate simulation, analysis results (snapshots and mass density profile) of the dissociation simulations show that lecithin-hydrate dissociates more slowly.

scholarly journals Conformational Ensembles of an Intrinsically Disordered Protein pKID with and without a KIX Domain in Explicit Solvent Investigated by All-Atom Multicanonical Molecular Dynamics

Biomolecules ◽  
2012 ◽  
Vol 2 (1) ◽  
pp. 104-121 ◽  
Author(s):  
Koji Umezawa ◽  
Jinzen Ikebe ◽  
Mitsunori Takano ◽  
Haruki Nakamura ◽  
Junichi Higo
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Site ◽  
Complex Structure ◽  
Intrinsically Disordered Protein ◽  
Bound State ◽  
Conformational Ensembles ◽  
Intrinsically Disordered ◽  
Dynamics Simulations ◽  
High Flexibility

The phosphorylated kinase-inducible activation domain (pKID) adopts a helix–loop–helix structure upon binding to its partner KIX, although it is unstructured in the unbound state. The N-terminal and C-terminal regions of pKID, which adopt helices in the complex, are called, respectively, αA and αB. We performed all-atom multicanonical molecular dynamics simulations of pKID with and without KIX in explicit solvents to generate conformational ensembles. Although the unbound pKID was disordered overall, αA and αB exhibited a nascent helix propensity; the propensity of αA was stronger than that of αB, which agrees with experimental results. In the bound state, the free-energy landscape of αB involved two low free-energy fractions: native-like and non-native fractions. This result suggests that αB folds according to the induced-fit mechanism. The αB-helix direction was well aligned as in the NMR complex structure, although the αA helix exhibited high flexibility. These results also agree quantitatively with experimental observations. We have detected that the αB helix can bind to another site of KIX, to which another protein MLL also binds with the adopting helix. Consequently, MLL can facilitate pKID binding to the pKID-binding site by blocking the MLL-binding site. This also supports experimentally obtained results.

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