scholarly journals Developing C2-Aroyl Indoles as Novel Inhibitors of IDO1 and Understanding Their Mechanism of Inhibition via Mass Spectroscopy, QM/MM Calculations and Molecular Dynamics Simulation

2021 ◽  
Vol 9 ◽  
Author(s):  
Jyoti Chauhan ◽  
Srinivas R. Maddi ◽  
Kshatresh Dutta Dubey ◽  
Subhabrata Sen
Keyword(s):  
Mass Spectroscopy ◽  
Conformational Changes ◽  
Malignant Tumors ◽  
Liver Microsomes ◽  
Md Simulations ◽  
Significant Inhibition ◽  
Dynamics Simulation ◽  
Ring Cleavage ◽  
Mechanism Of Inhibition ◽  
Tryptophan Oxidation

Indoleamine-2,3-dioxygenase (IDO1) and tryptophan dioxygenases are two heme based metalloenzymes that catalyze the tryptophan oxidation reaction by inserting molecular dioxygen to cleave the pyrrole ring. The mechanism of such ring cleavage reaction is of carcinogenic importance as the malignant tumors recruit this mechanism for immune invasion. In the presence study, we have synthesized a Novel C2 aroyl indoles inhibitor, 8d, which shows significant inhibition of 180 nM at IC50 scale. The binding and conformational changes that transpire after inhibitor binding were thoroughly studied by molecular docking and MD simulations. The subsequent QM/MM (Quantum Mechanical/Molecular Mechanical) calculations were used to proposed the mechanism of inhibition. The QM/MM calculations show that the reaction proceeds via multistep processes where the dioxygen insertion to the substrate 8a is the rate determining process. Theoretical mechanism is further supported by mass spectroscopy, and drug metabolism/pharmacokinetics study (DMPK) and metabolic stability of compound 8d was investigated in rat and human liver microsomes.

SPECIFIC BINDING OF A SHORT miRNA SEQUENCE BY ZINC KNUCKLES OF Lin28: A MOLECULAR DYNAMICS SIMULATION STUDY

2013 ◽  
Vol 12 (08) ◽  
pp. 1341015
Author(s):  
CHENG TAN ◽  
WENFEI LI ◽  
WEI WANG
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Conformational Changes ◽  
Rna Binding ◽  
Specific Binding ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Mirna Sequence ◽  
Physiological Importance ◽  
Terminal Loop

Protein Lin28 recognizes pre-let-7 microRNAs (miRNAs) through direct interactions between its zinc-knuckle type zinc-finger (ZnF) domains and the terminal loop of pre-let-7, resulting in the inhibition of the synthesis of mature let-7 miRNAs. Despite the physiological importance, the involved conformational changes and energetic factors contributing to the binding affinity and specificity remain unclear. We conducted molecular dynamics (MD) simulations in conjunction with molecular mechanics/generalized born surface area (MM/GBSA) and energy decomposition calculations to investigate the RNA binding-induced conformational changes of the ZnFs and the residual level energetic factors that influence the binding affinity and specificity. We showed that the binding of the RNA results in the inter-domain conformational changes of the two ZnF domains, including changes of the spatial relationships of several nucleobase-binding amino acids. We also observed mutation-induced weakening of the affinity of the Lin28–pre-let-7 binding, which reveals the importance of the stacking interactions between the side-chains of Tyr140, His148, His162 and the bases of nucleic acid G2 and G5 in the specific recognition of pre-let-7 by the ZnFs of Lin28.

A MOLECULAR DYNAMICS SIMULATION STUDY OF CONFORMATIONAL CHANGES AND SOLVATION OF Aβ PEPTIDE IN TRIFLUOROETHANOL AND WATER

2009 ◽  
Vol 08 (02) ◽  
pp. 215-231 ◽  
Author(s):  
S. JALILI ◽  
M. AKHAVAN
Keyword(s):  
Molecular Dynamics ◽  
Secondary Structure ◽  
Conformational Changes ◽  
Pure Water ◽  
Sodium Dodecyl ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Amyloid Beta Peptide ◽  
Sodium Dodecyl Sulfate Micelle ◽  
Beta Peptide

Molecular dynamics (MD) simulations of amyloid beta peptide have been performed in aqueous solutions of trifluoroethanol with different concentrations. The amount of α-helical secondary structure increases when going from pure water to trifluoroethanol-rich solutions. The conformation obtained in 40% (v/v) trifluoroethanol solution is very similar to the experimental observations of beta peptide in sodium dodecyl sulfate micelle. In this solution, the peptide has two helical segments connected through a looped region. The C-terminal helix of beta peptide unfolds in pure water. The effect of trifluoroethanol on peptide's secondary structure has been explained using the properties calculated from MD trajectories.

Closing the gap: an atomistic structural and functional perspective of S. mansoni universal stress G4LZI3 protein in complex with phenolic compounds

2020 ◽  
Vol 17 ◽  
Author(s):  
Priscilla Masamba ◽  
Geraldene Munsamy ◽  
Abidemi Paul Kappo
Keyword(s):  
Phenolic Compounds ◽  
Conformational Changes ◽  
Stress Protein ◽  
Md Simulations ◽  
Binding Energies ◽  
Developmental Cycle ◽  
Structure Based Drug Design ◽  
Bioinformatic Tools ◽  
Drug Of Choice ◽  
Functional Perspective

Background: For decades, Praziquantel has been the undisputed drug of choice for all schistosome infections, but rising concerns due to the unelucidated mechanism of action of the drug and unavoidable reports of emerging drug resistant strains has necessitated the need for alternative treatment drug. Moreover, current apprehension has been reinforced by total dependence on the drug for treatment hence, the search for novel and effective anti-schistosomal drugs. Uses: This study made use of bioinformatic tools to determine the structural binding of the Universal G4LZI3 stress protein (USP) in complex with ten polyphenol compounds, thereby highlighting the effectiveness of these recently identified ‘lead’ molecules in the design of novel therapeutics targeted against schistosomiasis. Upregulation of the G4LZI3 USP throughout the schistosome multifaceted developmental cycle sparks interest in its potential role as a druggable target. The integration of in silico tools provides an atomistic perspective into the binding of potential inhibitors to target proteins. Conclusion: This study therefore, implemented the use of molecular dynamic (MD) simulations to provide functional and structural insight into key conformational changes upon binding of G4ZLI3 to these key phenolic compounds. Post-MD analyses revealed unique structural and conformational changes in the G4LZI3 protein in complex with curcumin and catechin respectively. These systems exhibited the highest binding energies, while the major interacting residues conserved in all the complexes provides a route map for structure-based drug design of novel compounds with enhanced inhibitory potency against the G4LZI3 protein. This study suggests an alternative approach for the development of anti-schistosomal drugs using natural compounds.

scholarly journals Correlation of membrane protein conformational and functional dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raghavendar Reddy Sanganna Gari ◽  
Joel José Montalvo‐Acosta ◽  
George R. Heath ◽  
Yining Jiang ◽  
Xiaolong Gao ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Conformational Changes ◽  
Single Channel ◽  
Conformational Dynamics ◽  
Md Simulations ◽  
High Temporal Resolution ◽  
Dependent Manner ◽  
Functional Dynamics ◽  
Ph Dependent ◽  
Open States

AbstractConformational changes in ion channels lead to gating of an ion-conductive pore. Ion flux has been measured with high temporal resolution by single-channel electrophysiology for decades. However, correlation between functional and conformational dynamics remained difficult, lacking experimental techniques to monitor sub-millisecond conformational changes. Here, we use the outer membrane protein G (OmpG) as a model system where loop-6 opens and closes the β-barrel pore like a lid in a pH-dependent manner. Functionally, single-channel electrophysiology shows that while closed states are favored at acidic pH and open states are favored at physiological pH, both states coexist and rapidly interchange in all conditions. Using HS-AFM height spectroscopy (HS-AFM-HS), we monitor sub-millisecond loop-6 conformational dynamics, and compare them to the functional dynamics from single-channel recordings, while MD simulations provide atomistic details and energy landscapes of the pH-dependent loop-6 fluctuations. HS-AFM-HS offers new opportunities to analyze conformational dynamics at timescales of domain and loop fluctuations.

scholarly journals Understanding Covalent Grafting of Nanotubes onto Polymer Nanocomposites: Molecular Dynamics Simulation Study

Sensors ◽  
2021 ◽  
Vol 21 (8) ◽  
pp. 2621
Author(s):  
Seunghwa Yang
Keyword(s):  
Molecular Dynamics ◽  
Load Transfer ◽  
Cell Model ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Covalent Grafting ◽  
Modelling Strategies ◽  
Multi Walled Carbon Nanotubes ◽  
Walled Carbon Nanotubes ◽  
External Loads

Here, we systematically interrogate the effects of grafting single-walled (SWNT) and multi-walled carbon nanotubes (MWNT) to polymer matrices by using molecular dynamics (MD) simulations. We specifically investigate key material properties that include interfacial load transfer, alteration of nanotube properties, and dispersion of nanotubes in the polymer matrix. Simulations are conducted on a periodic unit cell model of the nanocomposite with a straight carbon nanotube and an amorphous polyethylene terephthalate (PET) matrix. For each type of nanotube, either 0%, 1.55%, or 3.1% of the carbon atoms in the outermost nanotubes are covalently grafted onto the carbon atoms of the PET matrix. Stress-strain curves and the elastic moduli of nanotubes and nanocomposites are determined based on the density of covalent grafting. Covalent grafting promotes two rivalling effects with respect to altering nanotube properties, and improvements in interfacial load transfer in the nanocomposites are clearly observed. The enhanced interface enables external loads applied to the nanocomposites to be efficiently transferred to the grafted nanotubes. Covalent functionalization of the nanotube surface with PET molecules can alter the solubility of nanotubes and improve dispersibility. Finally, we discuss the current limitations and challenges in using molecular modelling strategies to accurately predict properties on the nanotube and polymers systems studied here.

scholarly journals Biofunctional Peptide FNIII14: Therapeutic Potential

Encyclopedia ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 350-359
Author(s):  
Motomichi Fujita ◽  
Manabu Sasada ◽  
Takuya Iyoda ◽  
Satoshi Osada ◽  
Hiroaki Kodama ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Extracellular Matrix ◽  
Conformational Changes ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Malignant Tumors ◽  
Β1 Integrin ◽  
Inactive Form ◽  
Functional Inactivation ◽  
Organ Fibrosis

Biofunctional peptide FNIII14, which is derived from the 14th fibronectin (FN) type III-like (FN-III) repeat of FN molecule, is capable of inhibiting cell adhesion to the extracellular matrix (ECM). This functional site is usually buried within the molecular structure of FN, but can be exposed by conformational changes and proteolytic cleavage. Peptide FNIII14 can induce a conformational change in β1-integrin from the active to the inactive form, causing functional inactivation. Based on this anti-adhesive activity, peptide FNIII14 exhibits therapeutic potential for several diseases such as metabolic diseases, organ fibrosis, and malignant tumors. Peptide FNIII14 blocks integrin-mediated signaling by a mechanism entirely distinct from that of conventional antagonisitic peptides, including Arg-Gly-Asp peptides that competitively inhibit the ECM binding of integrin.

Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications

2015 ◽  
Vol 43 (5) ◽  
pp. 1023-1032 ◽  
Author(s):  
Thomas Stockner ◽  
Anna Mullen ◽  
Fraser MacMillan
Keyword(s):  
Crystal Structures ◽  
Conformational Changes ◽  
Abc Transporters ◽  
Epr Spectroscopy ◽  
Structural Information ◽  
Dynamic Properties ◽  
Molecular System ◽  
Synergistic Effects ◽  
Md Simulations ◽  
Substrate Spectrum

ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented.

A Study on the Uniaxial Tension of FCC Metals at Nano Level Using MD

2008 ◽  
Vol 32 ◽  
pp. 255-258
Author(s):  
Bohayra Mortazavi ◽  
Akbar Afaghi Khatibi
Keyword(s):  
Molecular Dynamics ◽  
Uniaxial Tension ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Face Centered Cubic ◽  
Engineering Strain ◽  
Fcc Metals ◽  
Engineering Stress ◽  
Nano Science ◽  
Face Centered

Molecular Dynamics (MD) are now having orthodox means for simulation of matter in nano-scale. It can be regarded as an accurate alternative for experimental work in nano-science. In this paper, Molecular Dynamics simulation of uniaxial tension of some face centered cubic (FCC) metals (namely Au, Ag, Cu and Ni) at nano-level have been carried out. Sutton-Chen potential functions and velocity Verlet formulation of Noise-Hoover dynamic as well as periodic boundary conditions were applied. MD simulations at different loading rates and temperatures were conducted, and it was concluded that by increasing the temperature, maximum engineering stress decreases while engineering strain at failure is increasing. On the other hand, by increasing the loading rate both maximum engineering stress and strain at failure are increasing.

THEORETICAL INVESTIGATIONS ON ELUCIDATING FUNDAMENTAL MECHANISMS OF CATALYSIS AND DYNAMICS INVOLVED IN TRANSCRIPTION BY RNA POLYMERASE

2013 ◽  
Vol 12 (08) ◽  
pp. 1341005 ◽  
Author(s):  
FÁTIMA PARDO-AVILA ◽  
LIN-TAI DA ◽  
YING WANG ◽  
XUHUI HUANG
Keyword(s):  
Rna Polymerase ◽  
Conformational Changes ◽  
Normal Mode Analysis ◽  
Md Simulations ◽  
Mode Analysis ◽  
Transcription Process ◽  
Nucleotide Addition ◽  
Theoretical Investigations ◽  
State Models ◽  
Elongation Process

RNA polymerase is the enzyme that synthesizes RNA during the transcription process. To understand its mechanism, structural studies have provided us pictures of the series of steps necessary to add a new nucleotide to the nascent RNA chain, the steps altogether known as the nucleotide addition cycle (NAC). However, these static snapshots do not provide dynamic information of these processes involved in NAC, such as the conformational changes of the protein and the atomistic details of the catalysis. Computational studies have made efforts to fill these knowledge gaps. In this review, we provide examples of different computational approaches that have improved our understanding of the transcription elongation process for RNA polymerase, such as normal mode analysis, molecular dynamic (MD) simulations, Markov state models (MSMs). We also point out some unsolved questions that could be addressed using computational tools in the future.

Molecular Dynamics Simulation of a Pullout Test on a Carbon Nanotube in a Polymer Matrix

2014 ◽  
Vol 1700 ◽  
pp. 61-66
Author(s):  
Guttormur Arnar Ingvason ◽  
Virginie Rollin
Keyword(s):  
Molecular Dynamics ◽  
Polymer Matrix ◽  
Large Scale ◽  
Md Simulations ◽  
Dynamics Simulation ◽  
Atomistic Simulations ◽  
Polymer Molecules ◽  
Molecular Potential ◽  
Pull Out ◽  
Walled Carbon Nanotubes

ABSTRACTAdding single walled carbon nanotubes (SWCNT) to a polymer matrix can improve the delamination properties of the composite. Due to the complexity of polymer molecules and the curing process, few 3-D Molecular Dynamics (MD) simulations of a polymer-SWCNT composite have been run. Our model runs on the Large-scale Atomic/Molecular Massively Parallel Simulator (LAMMPS), with a COMPASS (Condensed phase Optimized Molecular Potential for Atomistic Simulations Studies) potential. This potential includes non-bonded interactions, as well as bonds, angles and dihedrals to create a MD model for a SWCNT and EPON 862/DETDA (Diethyltoluenediamine) polymer matrix. Two simulations were performed in order to test the implementation of the COMPASS parameters. The first one was a tensile test on a SWCNT, leading to a Young’s modulus of 1.4 TPa at 300K. The second one was a pull-out test of a SWCNT from an originally uncured EPON 862/DETDA matrix.

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