scholarly journals Origin of conformational dynamics in a globular protein

2019 ◽  
Vol 2 (1) ◽  
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 ◽  
Native Structure ◽  
In The Wild ◽  
Dynamics Simulations ◽  
The Impact

AbstractProtein structures are dynamic, undergoing 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 core-residue substitutions in DANCER-3, a streptococcal protein G domain β1 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 structure and the other allowing two new conformational states to be accessed on the energy landscape. Overall, our results show how dynamics can appear in a stable globular fold, a critical step in the molecular evolution of dynamics-linked functions.

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 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 Nucleosomal embedding reshapes the dynamics of abasic sites

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

ABSTRACTApurinic/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, 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 occurrence 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. This study paves the way towards an in silico mapping of DNA-protein cross-links.

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 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.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

The Impact Of Emotional Intelligence On Leadership Excellence Of Executive Empoloyees In Public Sector Organizationin Ampara District Of Sri Lanka

2019 ◽  
Vol 118 (9) ◽  
pp. 52-60
Author(s):  
Dr.S. Gunapalan ◽  
Dr.K. Maran
Keyword(s):  
Emotional Intelligence ◽  
Public Sector ◽  
Vital Role ◽  
Public Organization ◽  
Self Awareness ◽  
Public Sector Organization ◽  
Expression Of Emotion ◽  
Asking Questions ◽  
Private Sector Organizations ◽  
The Impact

Emotional Intelligence is play a vital role to decide  leadership excellence. So this paper to study the  impact of emotional intelligence on leadership excellence of executive employee in public sector organization.Hence the objective of this  research   is to identify the  impact of emotional intelligence on leadership excellence of executive employee in Public Sector Organization in Ampara districtof Sri Lanka.emotional intelligence includes the verbal and non-verbal appraisal and expression of emotion, the regulation of emotion in the self and others, and the utilization of emotional content in problem solving. Cook (2006)[1]. Emotional intelligence is one of the  essential skill for leaders to manage their subordinate. Accordingly although there is some research done under “Emotional intelligence on leadership excellence of the executive employee in the public organization in Ampara district so this study full filed the gap. Based on the analysis, Self-awareness, Self-management, Social-awareness and Relationship management are the positively affect to the Leadership excellence. So, executive employees should consider about the Emotions of their subordinators when they completing their targets. leaders should pay the attention for recognize the situation, hove to impact their feelings for the performance & recognized their own feelings. Leaders should consider and see their own emotions when they work with others by listening carefully, understand the person by asking questions, identifying non-verbal expressions and solving problems without helming someone’s. Leadersshould consider their subordinators emotions when they find a common idea, government should give to moderate freedom to executive employees in public organization to take the decision with competing the private sector organizations.

Monitoring the Structural Dynamics of U2 snRNA Via Single-Molecule Förster Resonance Energy Transfer

2018 ◽  
Author(s):  
Alexander Carl DeHaven
Keyword(s):  
Energy Transfer ◽  
Structural Dynamics ◽  
Single Molecule ◽  
Conformational Dynamics ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Förster Resonance Energy Transfer ◽  
U2 Snrna ◽  
Folding Dynamics ◽  
The Impact

This thesis contains four topic areas: a review of single-molecule microscropy methods and splicing, conformational dynamics of stem II of the U2 snRNA, the impact of post-transcriptional modifications on U2 snRNA folding dynamics, and preliminary findings on Mango aptamer folding dynamics.

Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
Author(s):  
Fortunatus C. Ezebuo ◽  
Ikemefuna C. Uzochukwu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Binding Energy ◽  
Binding Site ◽  
Conformational Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Conformational Selection ◽  
Hybrid Mechanism ◽  
Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

scholarly journals High Expression of KLF10 Is Associated with Favorable Survival in Patients with Oral Squamous Cell Carcinoma

Medicina ◽  
2020 ◽  
Vol 57 (1) ◽  
pp. 17
Author(s):  
Chung-Min Yeh ◽  
Yi-Ju Lee ◽  
Po-Yun Ko ◽  
Yueh-Min Lin ◽  
Wen-Wei Sung
Keyword(s):  
Survival Rate ◽  
Oral Cancer ◽  
Cancer Patients ◽  
Protective Factor ◽  
Female Gender ◽  
Vital Role ◽  
Cancer Stage ◽  
Independent Prognostic Marker ◽  
Oral Cancer Patients ◽  
The Impact

Background and objectives: Krüppel-like transcription factor 10 (KLF10) plays a vital role in regulating cell proliferation, including the anti-proliferative process, activation of apoptosis, and differentiation control. KLF10 may also act as a protective factor against oral cancer. We studied the impact of KLF10 expression on the clinical outcomes of oral cancer patients to identify its role as a prognostic factor in oral cancer. Materials and Methods: KLF10 immunoreactivity was analyzed by immunohistochemical (IHC) stain analysis in 286 cancer specimens from primary oral cancer patients. The prognostic value of KLF10 on overall survival was determined by Kaplan–Meier analysis and the Cox proportional hazard model. Results: High KLF10 expression was significantly associated with male gender and betel quid chewing. The 5-year survival rate was greater for patients with high KLF10 expression than for those with low KLF10 expression (62.5% vs. 51.3%, respectively; p = 0.005), and multivariate analyses showed that high KLF10 expression was the only independent factor correlated with greater overall patient survival. The significant correlation between high KLF10 expression and a higher 5-year survival rate was observed in certain subgroups of clinical parameters, including female gender, non-smokers, cancer stage T1, and cancer stage N0. Conclusions: KLF10 expression, detected by IHC staining, could be an independent prognostic marker for oral cancer patients.

Sign in / Sign up

Export Citation Format

Share Document