| 1. |
- Mudedla, Sathish Kumar, et al.
(författare)
-
Destabilization of amyloid fibrils on interaction with MoS2-based nanomaterials
- 2019
-
Ingår i: RSC Advances. - : ROYAL SOC CHEMISTRY. - 2046-2069. ; 9:3, s. 1613-1624
-
Tidskriftsartikel (refereegranskat)abstract
- The present work is motivated by the established concept that the structure and energetics of biomacromolecules can be modulated by confining their dimensions in the nanoscale. In particular, here we use force-field methods to understand the stability of amyloid fibrils at nanostructured interfaces, which can be useful for the development of new therapeutics for Alzheimer's disease. We explore the binding modes and structural properties of fibrils at the interface of molybdenum disulphide nanotubes and the nanosurface using classical molecular dynamics simulations. We find that in general the MoS2 materials induces disruptions in the structure of the amyloid fibrils where the beta sheet conformation of the fibrils changes to a turned conformation, and it is large in the case of nanotubes in comparison to the nanosurfaces. The intermolecular hydrogen bonds, hydrophilic and hydrophobic contacts between the monomer peptides in the fibril are reduced due to their adsorption onto the MoS2 materials, which results in a destabilization of the fibril. The destabilization of fibril is to some extent compensated for by the van der Waals interactions between the fibril and MoS2. Overall the results indicate that MoS2-based materials can be useful in inhibiting the aggregation of smaller protofibrils to matured fibrils and to bust the already formed fibrils. Therapeutic materials should not exhibit any cross interaction with other off-targets compounds. In order to test whether the MoS2 nanomaterial has any such effect we have studied its interaction with two additional biomacromolecules, the human serum albumin and p53 protein, and we report no significant changes in the secondary structure of these biomolecules. Through molecular docking studies we also established that the drug binding ability of HSA is not altered by its surface binding to MoS2 nanosurface.
|
|
| 2. |
- Muvva, Charuvaka, et al.
(författare)
-
Unraveling the Unbinding Pathways of Products Formed in Catalytic Reactions Involved in SIRT1-3 : A Random Acceleration Molecular Dynamics Simulation Study
- 2019
-
Ingår i: Journal of Chemical Information and Modeling. - : AMER CHEMICAL SOC. - 1549-9596 .- 1549-960X. ; 59:10, s. 4100-4115
-
Forskningsöversikt (refereegranskat)abstract
- Sirtuins are a family of nicotinamide adenine dinucleotide (NAD(+))-dependent enzymes, which undergo robust deacetylase activity, resulting in the production of nicotinamide. It is well known that nicotinamide, which is one of the products, can also act as an inhibitor for further deacetylation process by forming NAD(+) again. Hence, the removal of nicotinamide from sirtuins is a demanding process, and the mechanistic understanding of the process remains elusive. In this investigation, we have made an attempt to unravel the unbinding pathways of nicotinamide from SIRT1, SIRT2, and SIRT3 (SIRT1-3) using Random Acceleration Molecular Dynamics (RAMD) Simulations, and we have successfully identified various unbinding channels. The selectivity of the egression channel is determined by using a thorough analysis of the frequency of egression trajectories. Similarly, various inhibitors have been docked with the active sites of SIRT1-3, and their egression pathways have been investigated to understand whether they follow the same egression pathway as that of nicotinamide. The residues that are responsible for the unbinding pathways have been determined from the analysis of RAMD trajectories. From these results, it is clear that phenylalanine and histidine residues play major roles in the egression of inhibitors. Additionally, the key residues Leu, Pro, Met, Phe, Tyr, and Ile are found to control the release by acting as gateway residues. The role of these residues from different egression channels has been studied by carrying out mutations with alanine residue. This is the first report on sirtuins, which demonstrates the novel unbinding pathways for nicotinamide/inhibitors. This work provides new insights for developing more promising SIRT1-3 inhibitors.
|
|
