scholarly journals Collaborative Behavior of Urea and KI in Denaturing Protein Native Structure

2019 ◽  
Author(s):  
Qiang Shao ◽  
Jinan Wang ◽  
Weiliang Zhu
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonding ◽  
Structural Dynamics ◽  
Electrostatic Interactions ◽  
Side Chain ◽  
Mixed Solution ◽  
Native Structure ◽  
Indirect Influence ◽  
Collaborative Behavior ◽  
Dynamics Simulations

AbstractIn this work, the combined influence of urea and KI on protein native structure is quantitatively investigated through the comparative molecular dynamics simulations on the structural dynamics of a polypeptide of TRPZIP4 in a series of urea/KI mixed solutions (urea concentration: 4M, KI salt concentration: 0M-6M). The observed enhanced denaturing ability of urea/KI mixture can be explained by direct interactions of urea/K+/water towards protein (electrostatic and vdW interactions from urea and electrostatic interactions from K+ and water) and indirect influence of KI on the strengthened interaction of urea towards protein backbone and side-chain. The latter indirect influence is fulfilled through the weakening of hydrogen bonding network among urea and water by the appearance of K+–water and I—urea interactions. As a result, the denaturing ability enhancement of urea and KI mixed solution is induced by the collaborative behavior of urea and KI salt.

scholarly journals Trehalose Stabilizing Protein in a Water Replacement Scenario: Insights from Molecular Dynamics Simulation

2019 ◽  
Author(s):  
Qiang Shao ◽  
Jinan Wang ◽  
Weiliang Zhu
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonding ◽  
Pure Water ◽  
Dynamics Simulation ◽  
Mixed Solution ◽  
Water Replacement ◽  
Model Protein ◽  
Active Research ◽  
Dynamics Simulations ◽  
Water Hydrogen

AbstractHow trehalose has exceptional property in helping biomolecules preserve their native structures remains a subject of active research. Running molecular dynamics simulations on a model protein in low-concentrated trehalose solution and pure water, respectively, the present study verifies the ability of trehalose in stabilizing protein native structure and provides a comprehensive atomic-level picture of the molecular interactions among protein, trehalose, and water in their mixed solution. Trehalose directly interacts to and meanwhile affects the interactions between the other species via hydrogen bonding: 1) trehalose molecules are clustered through inter-molecular hydrogen bonding interaction; 2) trehalose forms hydrogen bond with water which influences the strength of water-water hydrogen bonding network but does not impair protein-water hydrogen bonding; 3) trehalose is accessible to form hydrogen bonds towards protein and simultaneously replace water molecules around protein which reduces the hydrogen bonding possibility from water to protein, in accordance with “water replacement” scenario.

Real-Space X-Ray Pair Distribution Function Analysis and Molecular-Dynamics Modelling of Diflunisal Channel Hydrates

2020 ◽  
Author(s):  
Anuradha Pallipurath ◽  
Francesco Civati ◽  
Jonathan Skelton ◽  
Dean Keeble ◽  
Clare Crowley ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Distribution Function ◽  
Structural Dynamics ◽  
First Principles ◽  
Pair Distribution Function ◽  
Function Analysis ◽  
Real Space ◽  
X Ray ◽  
Dynamics Modelling ◽  
Dynamics Simulations

X-ray pair distribution function analysis is used with first-principles molecular dynamics simulations to study the co-operative H<sub>2</sub>O binding, structural dynamics and host-guest interactions in the channel hydrate of diflunisal.

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 The role of side chains in the interaction of new antitumor pyrimidoacridinetriones with DNA: molecular dynamics simulations.

2000 ◽  
Vol 47 (1) ◽  
pp. 47-57 ◽  
Author(s):  
J Mazerski ◽  
I Antonini ◽  
S Martelli
Keyword(s):  
Molecular Dynamics ◽  
Rational Design ◽  
Md Simulations ◽  
Ring System ◽  
Side Chain ◽  
Side Chains ◽  
Intercalation Complex ◽  
Highly Active ◽  
Simulation Techniques ◽  
Dynamics Simulations

Pyrimidoacridinetriones (PATs) are a new group of highly active antitumor compounds. It seems reasonable to assume that, like for some other acridine derivatives, intercalation into DNA is a necessary, however not a sufficient condition for antitumor activity of these compounds. Rational design of new compounds of this chemotype requires knowledge about the structure of the intercalation complex, as well as about interactions responsible for its stability. Computer simulation techniques such as molecular dynamics (MD) may provide valuable information about these problems. The results of MD simulations performed for three rationally selected PATs are presented in this paper. The compounds differ in the number and position of side chains. Each of the compounds was simulated in two systems: i) in water, and ii) in the intercalation complex with the dodecamer duplex d(GCGCGCGCGCGC)2. The orientation of the side chain in relation to the ring system is determined by the position of its attachment. Orientation of the ring system inside the intercalation cavity depends on the number and position of side chain(s). The conformations of the side chain(s) of all PATs studied in the intercalation complex were found to be very similar to those observed in water.

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.

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