Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin–thyroxin complexation: Inhibitor modeling study through docking and molecular dynamics simulation

Banerjee, Avik; Bairagya, Hridoy R.; Mukhopadhyay, Bishnu P.; Nandi, Tapas K.; Mishra, Deepakkumar

doi:10.1016/j.jmgm.2013.04.010

Cited by 10 publications

(11 citation statements)

References 48 publications

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“…Again, the normalised B-factor of the water molecule at W4 is also high, which makes it unstable in its position. Two other water molecules (W5 and W6) have also been identified as conserved near the catalytic site, which are quite different from the previously reported conserved water molecule (W) involved in the thyroxin-TTR complexation (Banerjee et al, 2013). In few X-ray structures some other water molecules having low positional occupancy are also observed in the vicinity of Glu89 and His90.…”

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confidence: 71%

“…So, it is expected that water mediate interaction of the catalytic, thyroxin and RBP binding residues may play some important role in the structure, function and dynamics of the protein. Recently, two of such conserved water molecules have been identified which play an important role in hTTR-Thyroxin complexation (Banerjee, Bairagya, Mukhopadhyay, Nandi, & Mishra, 2013). The present analysis of different apo, holo and mutated X-ray structures of hTTR (crystallised at different conditions) along with some MD simulation studies may put some light on the water mediated recognition dynamics of the catalytic, thyroxin and RBP binding sites.…”

Section: Introductionmentioning

confidence: 87%

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An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin

Banerjee

Mukhopadhyay

2014

Journal of Biomolecular Structure and Dynamics

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Human transthyretin (hTTR) is a multifunctional protein involved in several amyloidogenic diseases. Besides transportation of thyroxin and vitamin-A, its role towards the catalysis of apolipoprotein-A1 and Aβ-peptide are also drawing interest. The role of water molecules in the catalytic mechanism is still unknown. Extensive analyses of 14 high-resolution X-ray structures of human transthyretin and MD simulation studies have revealed the presence of eight conserved hydrophilic centres near its catalytic zone which may be indispensable for the function, dynamics and stability of the protein. Three water molecules (W1, W2 and W3) form a cluster and play an important role in the recognition of the catalytic and RBP-binding residues. They also induce the reorganisation of the His88 for coupling with other catalytic residues (His90, Glu92). Another water molecule (W5) participate in inter-monomer recognition between the catalytic and thyroxin binding sites. The rest four water molecules (W6, W*, W(#) and W(†)) form a distorted tetrahedral cluster and impart stability to the catalytic core of hTTR. The conserved water mediated recognition dynamics of the different functional sites may provide some rational clues towards the understanding of the activity and mechanism of hTTR.

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confidence: 71%

Section: Introductionmentioning

confidence: 87%

An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin

Banerjee

Mukhopadhyay

2014

Journal of Biomolecular Structure and Dynamics

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“…Before being released into plasma, TTR is principally produced in liver, choroids plexus, and retina [ 1 – 4 ]. It is mainly a carrier protein that binds to retinol binding protein (RBP) to transport vitamin A in plasma and represents the leading transporter of thyroxine (T4) in cerebrospinal fluid (CSF) [ 5 – 7 ].…”

Section: Introductionmentioning

confidence: 99%

Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations

Foumthuim

Corazza

Berni

et al. 2018

BioMed Research International

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Molecular dynamics simulations are used in this work to probe the structural stability and the dynamics of engineered mutants of transthyretin (TTR), i.e., the double mutant F87M/L110M (MT-TTR) and the triple mutant F87M/L110M/S117E (3M-TTR), in relation to wild-type. Free energy analysis from end-point simulations and statistical effective energy functions are used to analyze trajectories, revealing that mutations do not have major impact on protein structure but rather on protein association, shifting the equilibria towards dissociated species. The result is confirmed by the analysis of 3M-TTR which shows dissociation within the first 10 ns of the simulation, indicating that contacts are lost at the dimer-dimer interface, whereas dimers (formed by monomers which pair to form two extended β-sheets) appear fairly stable. Overall the simulations provide a detailed view of the dynamics and thermodynamics of wild-type and mutant transthyretins and a rationale of the observed effects.

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“…Analyses of the MDsimulation trajectories of all apo and mutant structures reveal high residential frequency for both W11 and W36, except in PDB entries 1ttb and 1fhn (Table 4), which may be owing to the mutational effect. A recent study has also revealed the role of W11 and W36 in protein-ligand complexation (Banerjee et al, 2013). Hydrogen-bond interactions of the conserved water molecules in the ligand-binding cavity of hTTR.…”

Section: W1mentioning

confidence: 99%

“…Water molecules also play crucial roles in drug/inhibitor-protein complexation (Poornima & Dean, 1995). Again, water molecules sometimes control the ligandbinding propensity by their presence in and subsequent displacement from the protein active site (Banerjee et al, 2013). Several studies have already been reported on conserved water molecules in various biomolecular systems (Ogata & Wodak, 2002;Nandi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

The putative role of some conserved water molecules in the structure and function of human transthyretin

Banerjee

Dasgupta

Mukhopadhyay

et al. 2015

Acta Cryst D Biol Crystallogr

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Human transthyretin (hTTR) is a multifunctional protein that is involved in several neurodegenerative diseases. Besides the transportation of thyroxin and vitamin A, it is also involved in the proteolysis of apolipoprotein A1 and Aβ peptide. Extensive analyses of 32 high-resolution X-ray and neutron diffraction structures of hTTR followed by molecular-dynamics simulation studies using a set of 15 selected structures affirmed the presence of 44 conserved water molecules in its dimeric structure. They are found to play several important roles in the structure and function of the protein. Eight water molecules stabilize the dimeric structure through an extensive hydrogen-bonding network. The absence of some of these water molecules in highly acidic conditions (pH ≤ 4.0) severely affects the interfacial hydrogen-bond network, which may destabilize the native tetrameric structure, leading to its dissociation. Three pairs of conserved water molecules contribute to maintaining the geometry of the ligand-binding cavities. Some other water molecules control the orientation and dynamics of different structural elements of hTTR. This systematic study of the location, absence, networking and interactions of the conserved water molecules may shed some light on various structural and functional aspects of the protein. The present study may also provide some rational clues about the conserved water-mediated architecture and stability of hTTR.

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Conserved water mediated H-bonding dynamics of Ser117 and Thr119 residues in human transthyretin–thyroxin complexation: Inhibitor modeling study through docking and molecular dynamics simulation

Cited by 10 publications

References 48 publications

An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin

An insight to the conserved water mediated dynamics of catalytic His88 and its recognition to thyroxin and RBP binding residues in human transthyretin

Dynamics and Thermodynamics of Transthyretin Association from Molecular Dynamics Simulations

The putative role of some conserved water molecules in the structure and function of human transthyretin

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