scholarly journals Comparing Fragment Binding Poses Prediction Using HSP90 as a Key Study: When Bound Water Makes the Difference

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4651
Author(s):  
Giovanni Bolcato ◽  
Maicol Bissaro ◽  
Mattia Sturlese ◽  
Stefano Moro
Keyword(s):  
Academic Research ◽  
Bound Water ◽  
Computational Prediction ◽  
Binding Pocket ◽  
Binding Mode ◽  
Correct Prediction ◽  
Water Molecules ◽  
The Difference ◽  
Dynamics Simulations ◽  
Hsp 90

Fragment-Based Drug Discovery (FBDD) approaches have gained popularity not only in industry but also in academic research institutes. However, the computational prediction of the binding mode adopted by fragment-like molecules within a protein binding site is still a very challenging task. One of the most crucial aspects of fragment binding is related to the large amounts of bound waters in the targeted binding pocket. The binding affinity of fragments may not be sufficient to displace the bound water molecules. In the present work, we confirmed the importance of the bound water molecules in the correct prediction of the fragment binding mode. Moreover, we investigate whether the use of methods based on explicit solvent molecular dynamics simulations can improve the accuracy of fragment posing. The protein chosen for this study is HSP-90.

scholarly journals Icephobicity of Functionalized Graphene Surfaces

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Xiang-Xiong Zhang ◽  
Min Chen
Keyword(s):  
Molecular Dynamics ◽  
Freezing Temperature ◽  
Ice Nucleation ◽  
Chloride Ions ◽  
Water Molecules ◽  
Sodium Ions ◽  
Functionalized Graphene ◽  
Functionalized Surfaces ◽  
The Difference ◽  
Dynamics Simulations

Manipulating the ice nucleation ability of liquid water by solid surface is of fundamental importance, especially in the design of icephobic surfaces. In this paper, the icephobicity of graphene surfaces functionalized by sodium ions, chloride ions, or methane molecules is investigated using molecular dynamics simulations. The icephobicity of the surface is evaluated by the freezing temperature. The freezing temperature on surface functionalized by methane molecules decreases at first and then increases as a function of the number groups, while the freezing temperature increases monotonically as a function of the number groups upon surfaces functionalized by sodium ions or chloride ions. The difference can be partially explained by the potential morphologies near the surfaces. Additionally, the validity of indicating the ice nucleation ability of water molecules using the number of six rings in the system is examined. Current study shows that the ice nucleation upon functionalized surfaces is inhibited when compared with smooth graphene substrate, which proves the feasibility of changing the icephobicity of the surfaces by functionalizing with certain ions or molecules.

scholarly journals Dielectrometry of hydration of fl avin mononucleotide and DNA

2021 ◽  
Vol 26 (3) ◽  
pp. 46-53
Author(s):  
V. Kashpur ◽  
◽  
O. Khorunzhaya ◽  
D. Pesina ◽  
◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Bound Water ◽  
Free Water ◽  
Dna Interaction ◽  
Flavin Mononucleotide ◽  
Water Molecules ◽  
Extremely High Frequency ◽  
Aqueous Solvent ◽  
The Difference ◽  
Solvent Molecules

Subject and Purpose. The elucidation of the molecular mechanisms of action of biomolecules is necessary for the development of state-of-the-art means of diagnosing and treatment. Dielectric studies in the millimeter wave range are effective for puzzling out the nature of the interaction of biomolecules with a surrounding aqueous solvent. Flavin mononucleotide (FMN), which can kill microorganisms and destroy cancer cells, is of particular interest. The aim of the work is to recognize hydration effects (changes in the state of water molecules) in FMN solutions. Methods and Methodology. The complex dielectric permittivity (CDP) is measured in the EHF range. Knowing the difference between the CDP of FMN solution and the CDP of water we find the difference, D es , between the effective dielectric permittivities in terms of the Debye theory of polar liquids. Since the relaxation time of dipoles of bound water is one or two orders of magnitude longer than that of free water, the amount of the difference D es characterizes the hydration of biomolecules. At low concentrations, this difference is proportional to the number of bound water molecules. Results. It has been shown that approximately18 water molecules are bound to the FMN molecule. Groups of atoms as the most probable hydration centers (primarily due to the hydrogen bonds) have been indicated. As the pH decreases, the number of water molecules bound to the Flavin mononucleotide increases to 21. The study of the FMN–DNA solution has shown that one nucleotide accounts for 25–26 bound water molecules in total. However, composing hydration numbers assumes a quantity of components less than 20. An assumption is made that the additional components are due to the cooperative nature of the hydration, leading to the fact that even if some solvent molecules do not come into a direct contact with hydration centers, they are under the influence of biomolecules all the same. Conclusion. Extremely-high-frequency dielectrometry is an effective method of research into the interaction of biomolecules with a water-ionic solvent. A FMN hydration model has been proposed, which indicates probable hydration centers and tells a measure of their effect on the solvent. It has been found that the FMN with DNA interaction increases the number of bound water molecules per one nucleotide of the DNA. The obtained results have been compared to the existing models of the DNA with FMN interaction.

scholarly journals Kinesin motility is driven by subdomain dynamics

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Wonmuk Hwang ◽  
Matthew J Lang ◽  
Martin Karplus
Keyword(s):  
Molecular Dynamics ◽  
Atpase Activity ◽  
Binding Pocket ◽  
Water Molecules ◽  
The Core ◽  
Hydrolysis Products ◽  
Atomic Mechanism ◽  
Cellular Environment ◽  
Dynamics Simulations ◽  
Motility Cycle

The microtubule (MT)-associated motor protein kinesin utilizes its conserved ATPase head to achieve diverse motility characteristics. Despite considerable knowledge about how its ATPase activity and MT binding are coupled to the motility cycle, the atomic mechanism of the core events remain to be found. To obtain insights into the mechanism, we performed 38.5 microseconds of all-atom molecular dynamics simulations of kinesin-MT complexes in different nucleotide states. Local subdomain dynamics were found to be essential for nucleotide processing. Catalytic water molecules are dynamically organized by the switch domains of the nucleotide binding pocket while ATP is torsionally strained. Hydrolysis products are 'pulled' by switch-I, and a new ATP is 'captured' by a concerted motion of the α0/L5/switch-I trio. The dynamic and wet kinesin-MT interface is tuned for rapid interactions while maintaining specificity. The proposed mechanism provides the flexibility necessary for walking in the crowded cellular environment.

scholarly journals UHR PX and NPC studies of H-FABP water network with tiny perdeuterated crystals

2014 ◽  
Vol 70 (a1) ◽  
pp. C1200-C1200
Author(s):  
Alberto Podjarny ◽  
Matthew Blakeley ◽  
Michael Haertlein ◽  
Andre Mitschler ◽  
Alexandra Cousido-Siah ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Charge Distribution ◽  
Binding Pocket ◽  
Internal Cavity ◽  
Water Molecules ◽  
Fatty Acid Binding ◽  
X Ray ◽  
X Ray Crystallography ◽  
Internal Water ◽  
Dynamics Simulations

We have obtained very detailed information about the internal water molecules in the large internal cavity inside fatty acid binding (FABP) proteins , in the presence of bound fatty acids (FA), by Ultra High Resolution X-Ray Crystallography (UHR) to 0.7 Å and Neutron Protein Crystallography (NPC) to 1.9 Å using a "radically small" (V=0.05 mm3) crystal. These waters form a very well ordered dense cluster of 12 molecules, positioned between the hydrophilic internal wall of the cavity and the fatty acid molecule. This information has been used for a detailed electrostatic analysis based on the charge distribution description modeled in the multipole formalism and on the Atoms in Molecules theory. This information is also being used in molecular dynamics simulations of H-FABP and its complex with FA in order to quantify the energetic contribution of these internal waters to the binding energy. The experiment has been done with oleic acid, coming with the protein expressed in E. Coli. The results have been analyzed in order to understand the interactions between the FA, the internal water and the protein, and in particular the role played by the water molecules in determining the potency and specificity of FA binding to FABPs. The major tool for visualizing the water molecules inside the H-FABP cavity is UHR X-Ray Crystallography combined with NPC. UHR crystallographic structures give the positions of hydrogen and oxygen atoms for well-ordered water molecules. NPC determines hydrogen atom positions, particularly of water molecules which have multiple conformations, leading to the best possible crystallographic model. This model was then complemented by a transferred charge distribution to accurately determine the electrostatic and topological properties in the binding pocket, providing a description of the way water molecules in hydration layer contribute to the binding of ligand, which is essential to understand and model ligand binding.

scholarly journals Sunitinib inhibits RNase L by destabilizing its active dimer conformation

2020 ◽  
Vol 477 (17) ◽  
pp. 3387-3399 ◽  
Author(s):  
Jinle Tang ◽  
Yingjie Wang ◽  
Huan Zhou ◽  
Yuxin Ye ◽  
Manisha Talukdar ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Synergistic Effects ◽  
Binding Pocket ◽  
Binding Mode ◽  
Ribonuclease Activity ◽  
Atp Binding ◽  
Rnase L ◽  
Combined Use ◽  
Repeat Domain ◽  
Dynamics Simulations

The pseudokinase (PK) RNase L is a functional ribonuclease and plays important roles in human innate immunity. The ribonuclease activity of RNase L can be regulated by the kinase inhibitor sunitinib. The combined use of oncolytic virus and sunitinib has been shown to exert synergistic effects in anticancer therapy. In this study, we aimed to uncover the mechanism of action through which sunitinib inhibits RNase L. We solved the crystal structures of RNase L in complex with sunitinib and its analogs toceranib and SU11652. Our results showed that sunitinib bound to the ATP-binding pocket of RNase L. Unexpectedly, the αA helix linking the ankyrin repeat-domain and the PK domain affected the binding mode of sunitinib and resulted in an unusual flipped orientation relative to other structures in PDB. Molecular dynamics simulations and dynamic light scattering results support that the binding of sunitinib in the PK domain destabilized the dimer conformation of RNase L and allosterically inhibited its ribonuclease activity. Our study suggested that dimer destabilization could be an effective strategy for the discovery of RNase L inhibitors and that targeting the ATP-binding pocket in the PK domain of RNase L was an efficient approach for modulating its ribonuclease activity.

scholarly journals Step-wise Hydration of Magnesium by Four Water Molecules Precedes Phosphate Release in a Myosin Motor

2019 ◽  
Author(s):  
M.L. Mugnai ◽  
D. Thirumalai
Keyword(s):  
Molecular Motors ◽  
Atp Hydrolysis ◽  
Structural Similarity ◽  
Nucleotide Binding ◽  
Binding Pocket ◽  
Water Molecules ◽  
Myosin Vi ◽  
Phosphate Release ◽  
Myosin Motors ◽  
Dynamics Simulations

AbstractMolecular motors, such as myosin, kinesin, and dynein, convert the energy released by the hydrolysis of ATP into mechanical work, which allows them to undergo directional motion on cytoskeletal tracks. This process is achieved through synchronization between the catalytic activity of the motor and the associated changes in its conformation. A pivotal step in the chemomechanical transduction in myosin motors occurs after they bind to the actin filament, which triggers the release of phosphate (Pi, product of ATP hydrolysis) and the rotation of the lever arm. Here, we investigate the mechanism of phosphate release in myosin VI, which has been debated for over two decades, using extensive molecular dynamics simulations involving multiple trajectories each several μs long. Because the escape of phosphate is expected to occur on time-scales on the order of milliseconds in myosin VI, we observed Pi release only if the trajectories were initiated with a rotated phosphate inside the nucleotide binding pocket. The rotation provided the needed perturbation that enabled successful expulsions of Pi in several trajectories. Analyses of these trajectories lead to a robust mechanism of Pi release in the class of motors belonging to the myosin super family. We discovered that although Pi populates the traditional “back door” route, phosphate exits through various other gateways, thus establishing the heterogeneity in the escape routes. Remarkably, we observe that the release of phosphate is preceded by a step-wise hydration of the ADP-bound magnesium ion. In particular, the release of the anion occurred only after four water molecules hydrate the cation (Mg2+). By performing comparative structural analyses, we suggest that the hydration of magnesium is the key step in the phosphate release in a number of ATPases and GTPases that share a similar structure in the nucleotide binding pocket. Thus, nature may have evolved hydration of Mg2+ by discrete water molecules as a general molecular switch for Pi release, which is a universal step in the catalytic cycle of many machines which share little sequence or structural similarity.

BOUND WATER, INOSITOL, AND THE EFFECT OF X-RAYS ON ESCHERICHIA COLI

1964 ◽  
Vol 10 (6) ◽  
pp. 877-885 ◽  
Author(s):  
S. J. Webb ◽  
M. D. Dumasia
Keyword(s):  
Escherichia Coli ◽  
Bound Water ◽  
Free Water ◽  
Sharp Decrease ◽  
Water Molecules ◽  
X Rays ◽  
X Ray ◽  
Water Layers ◽  
The Difference ◽  
Escherichia Coli B

Aerosols of Escherichia coli B were subjected to 250 kv X-rays. It was found that maximal X-ray damage occurred at 70 to 80% relative humidity (R.H.). At these R.H. values only the water bound directly to cell macromolecules remains, and if the water layers were increased by using higher humidities, X-ray damage decreased. Also, at R.H. levels below 70% a sharp decrease in the sensitivity of the cells to the radiation occurred. Several chemicals known to protect cells against desiccation, ultraviolet, and X-ray damage were examined and of these i-inositol proved the most successful. The difference in the protective ability of these various compounds indicated that some protect cells against desiccation damage by retaining water, others by replacing bound-water molecules in macromolecular structure but those retaining water will not protect against X-rays. The results suggest that the physical removal or ionization of a strategic bound-water molecule by X-rays causes most of the cell deaths rather than ionizations occurring in the free water as the presence of the latter appears to offer cells a measure of protection.

Nanocomputational Observation of Interaction of Two Cytotoxins and Nanobio Membrane: Molecular Dynamics Simulation Study

2011 ◽  
Vol 110-116 ◽  
pp. 3888-3892
Author(s):  
N. Maftouni ◽  
M. Amininassab ◽  
F. Kowsari
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Molecular Dynamics Simulation ◽  
Dynamics Simulation ◽  
Water Molecules ◽  
Small Proteins ◽  
Steered Molecular Dynamics Simulation ◽  
The Difference ◽  
Dynamics Simulations ◽  
Naja Atra

Experimental observations have shown that cardio toxins (cobra cytotoxins), small proteins of three-fingered cytotoxin group, damage nanobiomembranes in different cells and vesicles. However, the molecular mechanism of this damage is not yet completely cleared. Molecular dynamics simulations have been used here to study the interaction of cardiotoxins A3 and A4 from Naja atra cobra venom with hydrated 1-palmitoyl-2-oleoyl-1-sn-3-phosphatidylcholine (POPC) lipid bilayer in two separate systems. Each of studied systems included one cytotoxin molecule, 128 lipid molecules (64 molecules in each monolayer) and 11817 water molecules. It has been found that the toxin interacts with zwitterionic bilayer formed by POPC. At the beginning of simulation the cytotoxins have been oriented toward nanobiomembrane surface by their loops’ tips. This orientation has changed during first 50 ns of classical molecular dynamics simulation for both of studied cytotoxins. The A3 toxin finally meets POPC nanobiomembrane with sides of loops near tips including cytotoxin region THR148 and VAL155. The A4 cytotoxin molecule has been finally oriented toward surface of nanobiomembrane with base and one of loop's tip including THR184, ARG186 and LEU158 amino acids, after 50 ns molecular dynamics simulation. Then 25 ns steered molecular dynamics simulation has been done for both of systems. The obtained data suggest that cytotoxin A3 meets the nanobiomembrane with sides of loops near tips and A4 meets POPC nanobiomembrane with base and one of loop's tips. The difference between final orientations of these two cytotoxins comes from the difference in the structure of them.

scholarly journals A different mechanism of C-type inactivation in the Kv-like KcsA mutant E71V

2021 ◽  
Author(s):  
Ahmed Rohaim ◽  
Bram J.A. Vermeulen ◽  
Jing Li ◽  
Felix Kümmerer ◽  
Federico Napoli ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Bound Water ◽  
Selectivity Filter ◽  
Structural Basis ◽  
Water Molecules ◽  
X Ray ◽  
Physiological Importance ◽  
Kv Channels ◽  
Dynamics Simulations

ABSTRACTA large class of K+ channels display a time-dependent phenomenon called C-type inactivation whereby prolonged activation by an external stimulus leads to a non-conductive conformation of the selectivity filter. C-type inactivation is of great physiological importance particularly in voltage-activated K+ channels (Kv), affecting the firing patterns of neurons and shaping cardiac action potentials. While understanding the molecular basis of inactivation has a direct impact on human health, its structural basis remains unresolved. Knowledge about C-type inactivation has been largely deduced from the pH-activated bacterial K+ channel KcsA, whose selectivity filter under inactivating conditions adopts a constricted conformation at the level of the central glycine (TTVGYGD) that is stabilized by tightly bound water molecules. However, C-type inactivation is highly sensitive to the molecular environment surrounding the selectivity filter in the pore domain, which is different in Kv channels than in the model KcsA. In particular, a glutamic acid residue at position 71 along the pore helix in KcsA is consistently substituted by a nonpolar valine in most Kv channels, suggesting that this side chain is an important molecular determinant of function. Here, a combination of X-ray crystallography, solid-state NMR and molecular dynamics simulations of the E71V mutant of KcsA is undertaken to explore the features associated with this Kv-like construct. In both X-ray and ssNMR data, it is observed that the filter of the Kv-like KcsA mutant does not adopt the familiar constricted conformation under inactivating conditions. Rather, the filter appears to adopt a conformation that is slightly narrowed and rigidified over its entire length. No structural inactivation water molecules are present. On the other hand, molecular dynamics simulations indicate that the familiar constricted conformation can nonetheless be stably established in the mutant channel. Together, these findings suggest that the Kv-like E71V mutation in the KcsA channel may be associated with different modes of C-type inactivation, showing that distinct selectivity filter environments entail distinct C-type inactivation mechanisms.

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