Alteration of ssRNA Torsion and Water Influx Into ssRNA Pocket in K309A and S247A mutations

2019 ◽  
Vol 15 ◽  
Author(s):  
I. Olaposi Omotuyi
Keyword(s):  
Hydrogen Bond ◽  
Salt Bridge ◽  
Binding Pocket ◽  
Dynamics Simulation ◽  
Lassa Virus ◽  
Partial Loss ◽  
Hydrogen Bond Interaction ◽  
Phosphodiester Bond ◽  
Water Influx ◽  
Mechanistic Basis

Background: Lassa virus (LV) infection is a endemic disease from West Africa posing threat to the entire world. A thorough understanding of the mechanistic workings of the genome products of LV may be key to developing drugs candidates for the treatment of LV infection. Methods: Molecular dynamics simulation has been used to provide insight into the mechanistic basis for total loss of ssRNA interaction in nucleoprotein (NP) K309A, partial loss in S247A, and no loss in S237A by following the hydrogen bond interaction, water influx into the ssRNA pocket and glycosidic torsion angle (?) of the ssRNA. Results: The results revealed that K309A mutation is associated with complete loss of salt-bridge interaction between lysine ?-amino and U4-O2P phosphodiester linkage but not in S237A where S247-OG atom played a redundant role. S247A is also associated with partial loss of hydrogen bond between OG atom of S247 and C5-O2P phosphodiester bond as T178-OG1 group seem to have a seemingly redundant interaction with C5-O2P. While S247A only is also associated with alteration of ? rotation in U6/C7, both K309A and S247 but not S237A is associated with increased water influx into the ssRNA binding pocket. Conclusion: K309A mutation may result in non-viable Lassa viron as loss of ssRNA interaction may negatively affect genome biochemistry, semi-viable Lassa viron in S247A mutation may be due to loss of 3D arrangement of ssRNA due to splayed out nucleotides.

scholarly journals Molecular Determinants of Ligand Residence in Galectin

2021 ◽  
Author(s):  
Jaya Krishna Koneru ◽  
Suman Sinha ◽  
Jagannath Mondal
Keyword(s):  
Binding Site ◽  
Specific Binding ◽  
Binding Pocket ◽  
Cellular Adhesion ◽  
Dynamics Simulation ◽  
Natural Ligand ◽  
Molecular Determinants ◽  
Galectin 3 ◽  
Synthetic Ligand ◽  
Mechanistic Basis

The recognition of carbohydrates by lectins play key roles in diverse cellular processes such as cellular adhesion, proliferation and apoptosis which makes it a promising therapeutic target against cancers. One of the most functionally active lectins, galectin-3 is distinctively known for its specific binding affinity towards β-galactoside. Despite the prevalence of high-resolution crystallographic structures, the mechanistic basis and the molecular determinants of the sugar recognition process by galectin-3 are currently elusive. Here we address this question by capturing the complete dynamical binding process of human galectin-3 with its native ligand N-acetyllactosamine (LacNAc) and one of its synthetic derivatives by unbiased Molecular Dynamics simulation. In our simulations, both the natural ligand LacNAc and its synthetic derivative, initially solvated in water, diffuse around the protein and eventually recognise the designated binding site at the S-side of galectin-3, in crystallographic precision and identifies key metastable intermediate ligand-states around the galectin on their course to eventual binding. The simulations highlight that the origin of the experimentally observed multi-fold efficacy of synthetically designed ligand-derivative over its native natural ligand LacNAc lies in the derivative's relatively longer residence time in the bound pocket. A kinetic analysis demonstrates that the LacNAc-derivative would be more resilient compared to the parent ligand against unbinding from the protein binding site. In particular, the analysis identifies that interactions of the binding pocket residues Trp181, Arg144 and Arg162 with the tetrafuorophenyl ring of the derivative as the key determinant for the synthetic ligand to latch into the pocket.

T‐705‐modified ssRNA in complex with Lassa virus nucleoprotein exhibits nucleotide splaying and increased water influx into the RNA‐binding pocket

2019 ◽  
Vol 93 (4) ◽  
pp. 544-555 ◽  
Author(s):  
Olaposi I. Omotuyi ◽  
Oyekanmi Nash ◽  
David Safronetz ◽  
Ayodeji A. Ojo ◽  
Tomisin H. Ogunwa ◽  
...  
Keyword(s):  
Rna Binding ◽  
Binding Pocket ◽  
Lassa Virus ◽  
Water Influx

scholarly journals Effect of single mutagenesis on the binding pocket of canine estrogen receptor alpha: Structure and binding affinity

2016 ◽  
Vol 2 (2) ◽  
pp. 116 ◽  
Author(s):  
Waraphan Toniti ◽  
Aekkapot Chamkasem ◽  
Panpanga Sangsuriya ◽  
Pranom Puchadapirom
Keyword(s):  
Hydrogen Bond ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Estrogen Therapy ◽  
Binding Pocket ◽  
Single Mutation ◽  
Hydrogen Bond Interaction ◽  
Receptor Alpha ◽  
Bond Interaction

Hormone-related mammary gland tumors are among the most commonly diagnosed neoplasms in female dogs. Estrogen enacts its biological roles through specific receptors known as estrogen receptors (ER). In human medicine, anti-estrogen therapy has become the gold standard in ER-positive breast tumors’ therapeutic regimen. The binding pocket of the canine estrogen receptor alpha (cERα) ligand binding domain comprises of three key amino acid residues including E354, G522 and L526, which stabilize the cERα-E2 interaction via hydrogen bonding. The side chain of E354 shares hydrogen bond interaction with the A ring of its natural ligand E2, whereas the main chain of G522 and L526 interact with the E2-D ring. The single mutation of the E354 aberrant, along with the hydrogen bond interaction between cERα and both ligands, leads to a variety of binding affinities. According to this <em>in silico</em> model, it may be concluded that E354 plays a role in the cERα activities. The effects of single mutants might need to be studied further <em>in vitro</em> and <em>in vivo</em>.

scholarly journals Rational thermostabilisation of four-helix bundle dimeric de novo proteins

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shin Irumagawa ◽  
Kaito Kobayashi ◽  
Yutaka Saito ◽  
Takeshi Miyata ◽  
Mitsuo Umetsu ◽  
...  
Keyword(s):  
Protein Design ◽  
De Novo ◽  
Protein Complexes ◽  
Salt Bridge ◽  
Dynamics Simulation ◽  
Saturation Mutagenesis ◽  
Helix Bundle ◽  
Stable Mutant ◽  
Four Helix Bundle ◽  
The Stability

AbstractThe stability of proteins is an important factor for industrial and medical applications. Improving protein stability is one of the main subjects in protein engineering. In a previous study, we improved the stability of a four-helix bundle dimeric de novo protein (WA20) by five mutations. The stabilised mutant (H26L/G28S/N34L/V71L/E78L, SUWA) showed an extremely high denaturation midpoint temperature (Tm). Although SUWA is a remarkably hyperstable protein, in protein design and engineering, it is an attractive challenge to rationally explore more stable mutants. In this study, we predicted stabilising mutations of WA20 by in silico saturation mutagenesis and molecular dynamics simulation, and experimentally confirmed three stabilising mutations of WA20 (N22A, N22E, and H86K). The stability of a double mutant (N22A/H86K, rationally optimised WA20, ROWA) was greatly improved compared with WA20 (ΔTm = 10.6 °C). The model structures suggested that N22A enhances the stability of the α-helices and N22E and H86K contribute to salt-bridge formation for protein stabilisation. These mutations were also added to SUWA and improved its Tm. Remarkably, the most stable mutant of SUWA (N22E/H86K, rationally optimised SUWA, ROSA) showed the highest Tm (129.0 °C). These new thermostable mutants will be useful as a component of protein nanobuilding blocks to construct supramolecular protein complexes.

scholarly journals Study on the interaction between catechin and cholesterol by the density functional theory

2020 ◽  
Vol 18 (1) ◽  
pp. 357-368
Author(s):  
Kaiwen Zheng ◽  
Kai Guo ◽  
Jing Xu ◽  
Wei Liu ◽  
Junlang Chen ◽  
...  
Keyword(s):  
Density Functional Theory ◽  
Hydrogen Bond ◽  
Charge Transfer ◽  
Density Functional ◽  
Antioxidant Properties ◽  
Micelle Formation ◽  
Aromatic Rings ◽  
Hydrogen Bond Interaction ◽  
Functional Theory ◽  
The Density Functional Theory

AbstractCatechin – a natural polyphenol substance – has excellent antioxidant properties for the treatment of diseases, especially for cholesterol lowering. Catechin can reduce cholesterol content in micelles by forming insoluble precipitation with cholesterol, thereby reducing the absorption of cholesterol in the intestine. In this study, to better understand the molecular mechanism of catechin and cholesterol, we studied the interaction between typical catechins and cholesterol by the density functional theory. Results show that the adsorption energies between the four catechins and cholesterol are obviously stronger than that of cholesterol themselves, indicating that catechin has an advantage in reducing cholesterol micelle formation. Moreover, it is found that the molecular interactions of the complexes are mainly due to charge transfer of the aromatic rings of the catechins as well as the hydrogen bond interactions. Unlike the intuitive understanding of a complex formed by hydrogen bond interaction, which is positively correlated with the number of hydrogen bonds, the most stable complexes (epicatechin–cholesterol or epigallocatechin–cholesterol) have only one but stronger hydrogen bond, due to charge transfer of the aromatic rings of catechins.

scholarly journals Atomic-level insights into the activation of nitrogen via hydrogen-bond interaction toward nitrogen photofixation

Chem ◽  
2021 ◽  
Author(s):  
Yue Xin ◽  
Sanmei Wang ◽  
Haibo Yuan ◽  
Tingting Hou ◽  
Wenkun Zhu ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Atomic Level ◽  
Hydrogen Bond Interaction ◽  
Bond Interaction
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