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 Molecular Dynamics Simulations of a Cytochrome P450 from Tepidiphilus thermophilus (P450-TT) Reveal How Its Substrate-Binding Channel Opens

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3614
Author(s):  
Abayomi S. Faponle ◽  
Anupom Roy ◽  
Ayodeji A. Adelegan ◽  
James W. Gauld
Keyword(s):  
Crystal Structure ◽  
Molecular Dynamics ◽  
Cytochrome P450 ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Organic Molecules ◽  
Side Chain ◽  
Relative Solvent Accessibility ◽  
Amino Acid Residues ◽  
Dynamics Simulations

Cytochrome P450s (P450) are important enzymes in biology with useful biochemical reactions in, for instance, drug and xenobiotics metabolisms, biotechnology, and health. Recently, the crystal structure of a new member of the CYP116B family has been resolved. This enzyme is a cytochrome P450 (CYP116B46) from Tepidiphilus thermophilus (P450-TT) and has potential for the oxy-functionalization of organic molecules such as fatty acids, terpenes, steroids, and statins. However, it was thought that the opening to its hitherto identified substrate channel was too small to allow organic molecules to enter. To investigate this, we performed molecular dynamics simulations on the enzyme. The results suggest that the crystal structure is not relaxed, possibly due to crystal packing effects, and that its tunnel structure is constrained. In addition, the simulations revealed two key amino acid residues at the mouth of the channel; a glutamyl and an arginyl. The glutamyl’s side chain tightens and relaxes the opening to the channel in conjunction with the arginyl’s, though the latter’s side chain is less dramatically changed after the initial relaxation of its conformations. Additionally, it was observed that the effect of increased temperature did not considerably affect the dynamics of the enzyme fold, including the relative solvent accessibility of the amino acid residues that make up the substrate channel wall even as compared to the changes that occurred at room temperature. Interestingly, the substrate channel became distinguishable as a prominent tunnel that is likely to accommodate small- to medium-sized organic molecules for bioconversions. That is, P450-TT has the ability to pass appropriate organic substrates to its active site through its elaborate substrate channel, and notably, is able to control or gate any molecules at the opening to this channel.

EFFECT OF pH ON STRUCTURE AND STABILITY OF COLLAGEN-LIKE PEPTIDE: INSIGHT FROM MOLECULAR DYNAMICS SIMULATION

2011 ◽  
Vol 10 (02) ◽  
pp. 245-259 ◽  
Author(s):  
SHANG-ZHI PU ◽  
WEN-HUA ZHANG ◽  
BI SHI
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Force Field ◽  
Dynamics Simulation ◽  
Side Chain ◽  
Crystallographic Structure ◽  
Amino Acid Residues ◽  
Effect Of Ph ◽  
Structure And Stability ◽  
Dynamics Simulations

Molecular dynamics simulations were carried out to investigate the effect of pH on structure and stability of collagen-like peptide. All simulations were performed using the consistent valence force field (CVFF) molecular mechanical force field and isothermal-isobaric ensemble (NPT). The initial geometries of the collagen-like peptide were from an X-ray crystallographic structure. Some analyses from the molecular dynamics trajectories have been completed. The results show that the diameter of collagen-like peptide increases and the volume swells obviously in basic environment; however, the size of peptide changes slightly in acidic environment. The stability of collagen-like peptide decreases in acid and basic environment comparing to neutral environment based on root mean square deviation (RMSD). The number of hydrogen bond formed by peptide has a tendency to decrease in both acidic and basic environment. The average of intra-molecular H-bond is minimal under basic condition, and the average of inter-molecular H-bond between amino acid residues and water molecules is minimal under acid condition. The radial distribution function (RDF) shows that side-chain oxygen atoms are easier to form hydrogen bonds with water than side-chain nitrogen atoms. The interaction of various amino acid residues with water is position dependent. Distance between two triple helices increases markedly under highly basic condition, but changes slightly under highly acidic condition.

scholarly journals New CHARMM force field parameters for dehydrated amino acid residues, the key to lantibiotic molecular dynamics simulations

RSC Advances ◽  
2014 ◽  
Vol 4 (89) ◽  
pp. 48621-48631 ◽  
Author(s):  
Eleanor R. Turpin ◽  
Sam Mulholland ◽  
Andrew M. Teale ◽  
Boyan B. Bonev ◽  
Jonathan D. Hirst
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Force Field ◽  
Molecular Dynamics Simulations ◽  
Amino Acid Residues ◽  
Charmm Force Field ◽  
Force Field Parameters ◽  
Dynamics Simulations

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

scholarly journals Molecular Dynamics Insight into the Lipid II Recognition by Type A Lantibiotics: Nisin, Epidermin, and Gallidermin

Micromachines ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1169
Author(s):  
Irina Panina ◽  
Amir Taldaev ◽  
Roman Efremov ◽  
Anton Chugunov
Keyword(s):  
Molecular Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Simultaneous Formation ◽  
Lipid Ii ◽  
Target Binding ◽  
Dynamics Simulations ◽  
Similar Conformation ◽  
Insight Into

Lanthionine-containing peptides (lantibiotics) have been considered as pharmaceutical candidates for decades, although their clinical application has been restricted. Most lantibiotics kill bacteria via targeting and segregating of the cell wall precursor—membrane-inserted lipid II molecule—in some cases accompanied by pores formation. Nisin-like lantibiotics specifically bind to pyrophosphate (PPi) moiety of lipid II with their structurally similar N-terminal thioether rings A and B. Although possessing higher pore-forming capability, nisin, in some cases, is 10-fold less efficient in vivo as compared to related epidermin and gallidermin peptides, differing just in a few amino acid residues within their target-binding regions. Here, using molecular dynamics simulations, we investigated atomistic details of intermolecular interactions between the truncated analogues of these peptides (residues 1–12) and lipid II mimic (dimethyl pyrophosphate, DMPPi). The peptides adopt similar conformation upon DMPPi binding with backbone amide protons orienting into a single center capturing PPi moiety via simultaneous formation of up to seven hydrogen bonds. Epidermin and gallidermin adopt the complex-forming conformation twice as frequent as nisin does, enhancing the binding by the lysine 4 side chain. Introduction of the similar residue to nisin in silico improves the binding, providing ideas for further design of prototypic antibiotics.

scholarly journals Polymorphisms at Amino Acid Residues 141 and 154 Influence Conformational Variation in Ovine PrP

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Sujeong Yang ◽  
Alana M. Thackray ◽  
Lee Hopkins ◽  
Tom P. Monie ◽  
David F. Burke ◽  
...  
Keyword(s):  
Amino Acid ◽  
Structural Changes ◽  
Classical Scrapie ◽  
Side Chain ◽  
Genotypic Differences ◽  
Amino Acid Side Chain ◽  
Atypical Scrapie ◽  
Amino Acid Residues ◽  
Structural Environment ◽  
Dynamics Simulations

Polymorphisms in ovine PrP at amino acid residues 141 and 154 are associated with susceptibility to ovine prion disease: Leu141Arg154 with classical scrapie and Phe141Arg154 and Leu141His154 with atypical scrapie. Classical scrapie is naturally transmissible between sheep, whereas this may not be the case with atypical scrapie. Critical amino acid residues will determine the range or stability of structural changes within the ovine prion protein or its functional interaction with potential cofactors, during conversion of PrPC to PrPSc in these different forms of scrapie disease. Here we computationally identified that regions of ovine PrP, including those near amino acid residues 141 and 154, displayed more conservation than expected based on local structural environment. Molecular dynamics simulations showed these conserved regions of ovine PrP displayed genotypic differences in conformational repertoire and amino acid side-chain interactions. Significantly, Leu141Arg154 PrP adopted an extended beta sheet arrangement in the N-terminal palindromic region more frequently than the Phe141Arg154 and Leu141His154 variants. We supported these computational observations experimentally using circular dichroism spectroscopy and immunobiochemical studies on ovine recombinant PrP. Collectively, our observations show amino acid residues 141 and 154 influence secondary structure and conformational change in ovine PrP that may correlate with different forms of scrapie.

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