Molecular dynamics simulations provide insights into the substrate specificity of FAOX family members

Rigoldi, Federica; Spero, Ludovica; Vedove, Andrea Dalle; Redaelli, Alberto; Parisini, Emilio; Gautieri, Alfonso

doi:10.1039/c6mb00405a

Cited by 16 publications

(15 citation statements)

References 72 publications

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“…For the analysis of the geometry of the tunnel, we removed the ions and water molecules that were included in the MD runs. In particular, we applied the same protocol developed in one of our previously published works 44 , which allowed us to identify the tunnel as a mean of the calculated tunnels in each frame of the MD trajectory. As a starting point for tunnel calculation we used the coordinate of the N5 atom of flavin, the enzyme’s cofactor.…”

Section: Resultsmentioning

confidence: 99%

“…We tested the 19 Amadoriase I variants (named SS01 to SS19), each with a different disulfide bond, using molecular dynamics (MD) simulations and we derived those putative sites where the introduction of an SS bond may enhance protein stability. The 19 molecular models were minimized and equilibrated following protocols used in previous studies 44 , 58 – 60 . Specifically, each variant was modelled using the AMBER99SBildn force field 61 for protein, water (TIP3P) and ions, while the FAD cofactor was modelled using the general amber force field (GAFF) 62 .…”

Section: Methodsmentioning

confidence: 99%

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Thermal stabilization of the deglycating enzyme Amadoriase I by rational design

Rigoldi

Donini

Giacomina

et al. 2018

Sci Rep

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Amadoriases are a class of FAD-dependent enzymes that are found in fungi, yeast and bacteria and that are able to hydrolyze glycated amino acids, cleaving the sugar moiety from the amino acidic portion. So far, engineered Amadoriases have mostly found practical application in the measurement of the concentration of glycated albumin in blood samples. However, these engineered forms of Amadoriases show relatively low absolute activity and stability levels, which affect their conditions of use. Therefore, enzyme stabilization is desirable prior to function-altering molecular engineering. In this work, we describe a rational design strategy based on a computational screening method to evaluate a library of potentially stabilizing disulfide bonds. Our approach allowed the identification of two thermostable Amadoriase I mutants (SS03 and SS17) featuring a significantly higher T50 (55.3 °C and 60.6 °C, respectively) compared to the wild-type enzyme (52.4 °C). Moreover, SS17 shows clear hyperstabilization, with residual activity up to 95 °C, whereas the wild-type enzyme is fully inactive at 55 °C. Our computational screening method can therefore be considered as a promising approach to expedite the design of thermostable enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Thermal stabilization of the deglycating enzyme Amadoriase I by rational design

Rigoldi

Donini

Giacomina

et al. 2018

Sci Rep

Self Cite

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“…Precisely designed MD simulations can frequently intercept the wrong interpretations of the obtained experimental results. Moreover, MD simulation can provide key information at the atomistic levels when the experimental methods have some limitations or are incapable (Masic et al, 2015; Rigoldi et al, 2016; Tokareva et al, 2014). Therefore, it can be extremely advantageous in providing physical and chemical intuition to design the biosensors with the highest efficiency.…”

Section: Computational Methods For Biosensor Designmentioning

confidence: 99%

Recent advances in computational methods for biosensor design

Khoshbin

Housaindokht

Izadyar

et al. 2020

Biotech & Bioengineering

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Biosensors are analytical tools with a great application in healthcare, food quality control, and environmental monitoring. They are of considerable interest to be designed by using cost‐effective and efficient approaches. Designing biosensors with improved functionality or application in new target detection has been converted to a fast‐growing field of biomedicine and biotechnology branches. Experimental efforts have led to valuable successes in the field of biosensor design; however, some deficiencies restrict their utilization for this purpose. Computational design of biosensors is introduced as a promising key to eliminate the gap. A set of reliable structure prediction of the biosensor segments, their stability, and accurate descriptors of molecular interactions are required to computationally design biosensors. In this review, we provide a comprehensive insight into the progress of computational methods to guide the design and development of biosensors, including molecular dynamics simulation, quantum mechanics calculations, molecular docking, virtual screening, and a combination of them as the hybrid methodologies. By relying on the recent advances in the computational methods, an opportunity emerged for them to be complementary or an alternative to the experimental methods in the field of biosensor design.

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“…The systems were modeled following protocols described in previous studies [33,34,35,36,37]. They were all minimized and equilibrated for 100 ps using the NAMD code [38] under constant pressure and temperature (NPT) to relax the volume of the periodic box.…”

Section: Methodsmentioning

confidence: 99%

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

Gautieri

Beeg

Gobbi

et al. 2019

IJMS

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The pathological aggregation of amyloidogenic proteins is a hallmark of many neurological diseases, including Alzheimer’s disease and prion diseases. We have shown both in vitro and in vivo that doxycycline can inhibit the aggregation of Aβ42 amyloid fibrils and disassemble mature amyloid fibrils. However, the molecular mechanisms of the drug’s anti-amyloidogenic property are not understood. In this study, a series of molecular dynamics simulations were performed to explain the molecular mechanism of the destabilization of Aβ42 fibrils by doxycycline and to compare the action of doxycycline with those of iododoxorubicin (a toxic structural homolog of tetracyclines), curcumin (known to have anti-amyloidogenic activity) and gentamicin (an antibiotic with no experimental evidence of anti-amyloidogenic properties). We found that doxycycline tightly binds the exposed hydrophobic amino acids of the Aβ42 amyloid fibrils, partly leading to destabilization of the fibrillar structure. Clarifying the molecular determinants of doxycycline binding to Aβ42 may help devise further strategies for structure-based drug design for Alzheimer’s disease.

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Molecular dynamics simulations provide insights into the substrate specificity of FAOX family members

Cited by 16 publications

References 72 publications

Thermal stabilization of the deglycating enzyme Amadoriase I by rational design

Thermal stabilization of the deglycating enzyme Amadoriase I by rational design

Recent advances in computational methods for biosensor design

The Anti-Amyloidogenic Action of Doxycycline: A Molecular Dynamics Study on the Interaction with Aβ42

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