scholarly journals Structural, Dynamical, and Energetical Consequences of Rett Syndrome Mutation R133C in MeCP2

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Tugba G. Kucukkal ◽  
Emil Alexov
Keyword(s):  
Rett Syndrome ◽  
Experimental Studies ◽  
Common Disease ◽  
Salt Bridges ◽  
Wild Type ◽  
Disease Mechanism ◽  
Neurodevelopmental Disease ◽  
Mecp2 Protein ◽  
Dynamics Simulations ◽  
The Impact

Rett Syndrome (RTT) is a progressive neurodevelopmental disease affecting females. RTT is caused by mutations in theMECP2gene and various amino acid substitutions have been identified clinically in different domains of the multifunctional MeCP2 protein encoded by this gene. The R133C variant in the methylated-CpG-binding domain (MBD) of MeCP2 is the second most common disease-causing mutation in the MBD. Comparative molecular dynamics simulations of R133C mutant and wild-type MBD have been performed to understand the impact of the mutation on structure, dynamics, and interactions of the protein and subsequently understand the disease mechanism. Two salt bridges within the protein and two critical hydrogen bonds between the protein and DNA are lost upon the R133C mutation. The mutation was found to weaken the interaction with DNA and also cause loss of helicity within the 141-144 region. The structural, dynamical, and energetical consequences of R133C mutation were investigated in detail at the atomic resolution. Several important implications of this have been shown regarding protein stability and hydration dynamics as well as its interaction with DNA. The results are in agreement with previous experimental studies and further provide atomic level understanding of the molecular origin of RTT associated with R133C variant.

scholarly journals Molecular Dynamics Approach in the Comparison of Wild-Type and Mutant Paraoxonase-1 Apoenzyme Form

2015 ◽  
Vol 9 ◽  
pp. BBI.S25626 ◽  
Author(s):  
Khadija Amine ◽  
Lamia Miri ◽  
Adil Naimi ◽  
Rachid Saile ◽  
Abderrahmane El Kharrim ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Active Site ◽  
Paraoxonase 1 ◽  
Wild Type ◽  
Repetitive Movement ◽  
Catalytic Core ◽  
In The Wild ◽  
Dynamics Simulations ◽  
L1 And L2 ◽  
The Impact

There is some evidence linking the mammalian paraoxonase-1 (PON1) loops (L1 and L2) to an increased flexibility and reactivity of its active site with potential substrates. The aim of this work is to study the structural, dynamical, and functional effects of the most flexible regions close to the active site and to determine the impact of mutations on the protein. For both models, wild-type (PON1wild) and PON1 mutant (PON1mut) models, the L1 loop and Q/R and L/M mutations were constructed using MODELLER software. Molecular dynamics simulations of 20 ns at 300 K on fully modeled PON1wild and PON1mut apoenzyme have been done. Detailed analyses of the root-mean-square deviation and fluctuations, H-bonding pattern, and torsion angles have been performed. The PON1wild results were then compared with those obtained for the PON1mut. Our results show that the active site in the wild-type structure is characterized by two distinct movements of opened and closed conformations of the L1 and L2 loops. The alternating and repetitive movement of loops at specific times is consistent with the presence of 11 defined hydrogen bonds. In the PON1mut, these open-closed movements are therefore totally influenced and repressed by the Q/R and L/M mutations. In fact, these mutations seem to impact the PON1mut active site by directly reducing the catalytic core flexibility, while maintaining a significant mobility of the switch regions delineated by the loops surrounding the active site. The impact of the studied mutations on structure and dynamics proprieties of the protein may subsequently contribute to the loss of both flexibility and activity of the PON1 enzyme.

scholarly journals Origin of Conformational Dynamics in a Globular Protein

2019 ◽  
Author(s):  
Adam M. Damry ◽  
Marc M. Mayer ◽  
Aron Broom ◽  
Natalie K. Goto ◽  
Roberto A. Chica
Keyword(s):  
Conformational Dynamics ◽  
Protein Structures ◽  
Vital Role ◽  
Globular Protein ◽  
Conformational Exchange ◽  
Solution Nmr ◽  
Wild Type ◽  
In The Wild ◽  
Dynamics Simulations ◽  
The Impact

AbstractProtein structures are dynamic, undergoing specific motions that can play a vital role in function. However, the link between primary sequence and conformational dynamics remains poorly understood. Here, we studied how conformational dynamics can arise in a globular protein by evaluating the impact of individual substitutions of core residues in DANCER-3, a streptococcal protein G domain β1 (Gβ1) variant that we previously designed to undergo a specific mode of conformational exchange that has never been observed in the wild-type protein. Using a combination of solution NMR experiments and molecular dynamics simulations, we demonstrate that only two mutations are necessary to create this conformational exchange, and that these mutations work synergistically, with one destabilizing the native Gβ1 structure and the other allowing two new conformational states to be accessed on the energy landscape. Overall, our results show how conformational dynamics can appear in a stable globular fold, a critical step in the molecular evolution of new dynamics-linked functions.

scholarly journals The Effect of Multisite Phosphorylation on the Conformational Properties of Intrinsically Disordered Proteins

2021 ◽  
Vol 22 (20) ◽  
pp. 11058
Author(s):  
Ellen Rieloff ◽  
Marie Skepö
Keyword(s):  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Salt Bridges ◽  
Intrinsically Disordered ◽  
Local Contraction ◽  
Charged Residues ◽  
Common Strategy ◽  
Disordered Peptides ◽  
Dynamics Simulations ◽  
The Impact

Intrinsically disordered proteins are involved in many biological processes such as signaling, regulation, and recognition. A common strategy to regulate their function is through phosphorylation, as it can induce changes in conformation, dynamics, and interactions with binding partners. Although phosphorylated intrinsically disordered proteins have received increased attention in recent years, a full understanding of the conformational and structural implications of phosphorylation has not yet been achieved. Here, we present all-atom molecular dynamics simulations of five disordered peptides originated from tau, statherin, and β-casein, in both phosphorylated and non-phosphorylated state, to compare changes in global dimensions and structural elements, in an attempt to gain more insight into the controlling factors. The changes are in qualitative agreement with experimental data, and we observe that the net charge is not enough to predict the impact of phosphorylation on the global dimensions. Instead, the distribution of phosphorylated and positively charged residues throughout the sequence has great impact due to the formation of salt bridges. In statherin, a preference for arginine–phosphoserine interaction over arginine–tyrosine accounts for a global expansion, despite a local contraction of the phosphorylated region, which implies that also non-charged residues can influence the effect of phosphorylation.

scholarly journals Analysing the impact of the two most common SARS-CoV-2 nucleocapsid protein variants on interactions with membrane protein in silico

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Syeda Tasnim Quayum ◽  
Saam Hasan
Keyword(s):  
Membrane Protein ◽  
In Silico ◽  
Nucleocapsid Protein ◽  
The Body ◽  
M Protein ◽  
Mutant Protein ◽  
Salt Bridges ◽  
Wild Type ◽  
In Silico Studies ◽  
The Impact

AbstractAs the body of scientific research focusing on the severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 continues to grow, several mutations have been reported as very common across the globe. In this study, we analysed the SARS-CoV-2 nucleocapsid protein (N protein) with respect to the widely observed 28881-28883 GGG to AAC variant. One of the major functions of the SARS-CoV-2 nucleocapsid protein is virion packaging through its interactions with the membrane protein (M protein). Our goal was to investigate, using in silico studies, the interaction between the mutant nucleocapsid protein and the M protein and how it differed from that of wild type N-M protein interaction. The results showed significant differences in interactions between the two. The mutant protein was predicted to form 3 salt bridges with the M protein, while the wild type only formed 2. The mutant protein was also predicted to display less temperature sensitivity than its wild type counterpart.

scholarly journals Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy

2021 ◽  
Author(s):  
Juan Qin ◽  
Jingfeng Zhang ◽  
Lianyun Lin ◽  
Omid Haji-Ghassemi ◽  
Zhi Lin ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Calcium Uptake ◽  
Catalytic Domain ◽  
Common Disease ◽  
Wild Type ◽  
Disease Mechanism ◽  
Familial Dilated Cardiomyopathy ◽  
Phosphorylation Level ◽  
Biochemical Assays ◽  
Fight Or Flight Response

Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. PLN interacts with sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and regulates calcium uptake, which is modulated by the protein kinase A (PKA)-dependent phosphorylation of PLN during the fight-or-flight response. Here, we present the crystal structures of the catalytic domain of PKA in complex with wild-type and DCM-mutant PLNs. Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. In addition, we demonstrate that another more ubiquitous SERCA-regulatory peptide, called another-regulin (ALN), shares a similar mechanism mediated by PKA in regulating SERCA activity.

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 time of strong actomyosin binding depends on electrostatic interactions within the force generating region in human cardiac myosin

2020 ◽  
Author(s):  
Akhil Gargey ◽  
Shiril Bhardwaj Iragavarapu ◽  
Alexander V. Grdzelishvili ◽  
Yuri E. Nesmelov
Keyword(s):  
Electrostatic Interactions ◽  
Myosin Head ◽  
Bound State ◽  
Myosin Isoforms ◽  
Salt Bridges ◽  
Cardiac Myosin ◽  
Wild Type ◽  
Transient Kinetics ◽  
Adp Release ◽  
Dynamics Simulations

AbstractTwo single mutations, R694N and E45Q, were introduced in the beta isoform of human cardiac myosin to remove permanent salt bridges E45:R694 and E98:R694 in the force-generating region of myosin head. Beta isoform-specific bridges E45:R694 and E98:R694 were discovered in the molecular dynamics simulations of the alpha and beta myosin isoforms. Alpha and beta isoforms exhibit different kinetics, ADP dissociates slower from actomyosin containing beta myosin isoform, therefore, beta myosin stays strongly bound to actin longer. We hypothesize that the electrostatic interactions in the force-generating region modulate affinity of ADP to actomyosin, and therefore, the time of the strong actomyosin binding. Wild type and the mutants of the myosin head construct (1-843 amino acid residues) were expressed in differentiated C2C12 cells, and duration of the strongly bound state of actomyosin was characterized using transient kinetics spectrophotometry. All myosin constructs exhibited a fast rate of ATP binding to actomyosin and a slow rate of ADP dissociation, showing that ADP release limits the time of the strongly bound state of actomyosin. Mutant R694N showed faster rate of ADP release from actomyosin, compared to the wild type and the E45Q mutant, thus confirming that electrostatic interactions within the force-generating region of human cardiac myosin regulate ADP release and the duration of the strongly bound state of actomyosin.

scholarly journals Effect of cholesterol vs. ergosterol on DPPC bilayer properties: insights from atomistic simulations

2020 ◽  
Author(s):  
A. Alavizargar ◽  
F. Keller ◽  
A. Heuer
Keyword(s):  
Lipid Rafts ◽  
Binary Mixtures ◽  
Experimental Studies ◽  
Yeast Cells ◽  
Planar Structure ◽  
Therapeutic Drugs ◽  
Dppc Bilayer ◽  
Dynamics Simulations ◽  
The Impact ◽  
Two Sides

AbstractCholesterol and ergosterol are two dominant sterols in the membranes of eukaryotic and yeast cells, respectively. Although their chemical structure is very similar, their impact on the structure and dynamics of membranes differs. In this work, we have explored the effect of these two sterols on binary mixtures with 1,2-dipalnitoyl-sn-glycerol-3-phosphocholine (DPPC) lipid bilayer at various sterol concentration and temperatures, employing molecular dynamics simulations. The simulations revealed that cholesterol has a stronger impact on the ordering of the lipid chains and leads to more condensed membranes with respect to ergosterol. This difference likely arises from a more planar structure of the ring part as well as the better alignment of cholesterol among the DPPC chains with respect to ergosterol. The degree of the planarity of the ring system affects the orientation of the methyl groups on the rough side and distribute the lipid chains on the two sides of the sterols differently. Similar to the structural observations, cholesterol also has a stronger influence on the dynamics, and consistently, establishes stronger DPPC-sterol interactions when compared to ergosterol. Although our findings are consistent with some previous simulations as well as recent experiments, they are at odds with some other studies. Therefore, the presented results may shed new lights on the impact of sterols on the saturated lipids bilayers with implications for binary mixtures of lipids as well as lipid rafts.SignificanceCholesterol and ergosterol are crucial lipid molecules of eukaryotic and prokaryotic cells, respectively, with an important role for the characteristics of the membranes. Surprisingly, many experimental studies have reported opposing results concerning their relative impact. Our work aims to understand the molecular mechanism behind the influence of these sterols on the properties of saturated DPPC chains via a systematic computational approach at atomic resolution. The results show that cholesterol has a higher impact on the ordering, condensing and dynamics of the lipid chains and closely interact with them due to its more planar structure as compared to ergosterol. These effects can have implications in lipid rafts and the interaction of therapeutic drugs with membranes.

scholarly journals Nucleosomal embedding reshapes the dynamics of abasic sites

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Emmanuelle Bignon ◽  
Victor E. P. Claerbout ◽  
Tao Jiang ◽  
Christophe Morell ◽  
Natacha Gillet ◽  
...  
Keyword(s):  
Conformational Dynamics ◽  
Experimental Studies ◽  
Dna Lesions ◽  
Nucleosome Core ◽  
Abasic Sites ◽  
Cross Links ◽  
Ap Sites ◽  
Base Excision ◽  
Dynamics Simulations ◽  
The Impact

Abstract Apurinic/apyrimidinic (AP) sites are the most common DNA lesions, which benefit from a most efficient repair by the base excision pathway. The impact of losing a nucleobase on the conformation and dynamics of B-DNA is well characterized. Yet AP sites seem to present an entirely different chemistry in nucleosomal DNA, with lifetimes reduced up to 100-fold, and the much increased formation of covalent DNA-protein cross-links leading to strand breaks, refractory to repair. We report microsecond range, all-atom molecular dynamics simulations that capture the conformational dynamics of AP sites and their tetrahydrofuran analogs at two symmetrical positions within a nucleosome core particle, starting from a recent crystal structure. Different behaviours between the deoxyribo-based and tetrahydrofuran-type abasic sites are evidenced. The two solvent-exposed lesion sites present contrasted extrahelicities, revealing the crucial role of the position of a defect around the histone core. Our all-atom simulations also identify and quantify the frequency of several spontaneous, non-covalent interactions between AP and positively-charged residues from the histones H2A and H2B tails that prefigure DNA-protein cross-links. Such an in silico mapping of DNA-protein cross-links gives important insights for further experimental studies involving mutagenesis and truncation of histone tails to unravel mechanisms of DPCs formation.

scholarly journals In vivo repair of a protein underlying a neurological disorder by programmable RNA editing

2020 ◽  
Author(s):  
John R Sinnamon ◽  
Susan Y Kim ◽  
Jenna R Fisk ◽  
Zhen Song ◽  
Hiroyuki Nakai ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rna Editing ◽  
Neurological Disease ◽  
Catalytic Domain ◽  
Wild Type ◽  
Adeno Associated Virus ◽  
Base Editing ◽  
Neurodevelopmental Disease ◽  
Mecp2 Protein

AbstractRNA base editing is gaining momentum as an approach to repair mutations, but its application to neurological disease has not been established. We have succeeded in directed transcript editing of a pathological mutation in a mouse model of the neurodevelopmental disease, Rett syndrome. Specifically, we directed editing of a guanosine to adenosine mutation in RNA encoding Methyl CpG Binding Protein 2 (MECP2). Repair was mediated by injecting the hippocampus of juvenile Rett mice with an adeno-associated virus expressing both an engineered enzyme containing the catalytic domain of Adenosine Deaminase Acting on RNA 2 and a Mecp2 targeting guide. After one month, 50% of Mecp2 RNA was recoded in three different hippocampal neuronal subtypes, and the ability of MeCP2 protein to associate with heterochromatin was similarly restored to 50% of wild-type levels. This study represents the first in vivo programmable RNA editing applied to a model of neurological disease.

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