Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations

Moonsamy, Suri; Bhakat, Soumendranath; Walker, Ross C.; Soliman, Mahmoud E. S.

doi:10.1007/s12013-015-0709-2

Cited by 8 publications

(2 citation statements)

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“…To examine the flap dynamics of apo and bound cathepsin‐D, a multiple molecular dynamics (MD) trajectory approach was performed. Although a continuous MD trajectory approach could result in discrepancies such as high statistical errors arising from denatured protein configuration during a simulation; a multiple‐MD trajectory approach is, therefore, more reliable with reduced force field‐induced discrepancies, statistical bias and computational duration [Kanibolotsky et al, ; Moonsamy et al, ]. In this study, a multiple‐MD trajectory approach was performed from four distinctive MD runs for a period of 50 ns with different respective initial velocities as illustrated in Figure .…”

Section: Methodsmentioning

confidence: 99%

Molecular Dynamics Simulations of Ligand‐Induced Flap Conformational Changes in Cathepsin‐D—A Comparative Study

Arodola

Soliman

2016

J of Cellular Biochemistry

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The flap region in aspartic proteases is a unique structural feature to this class of enzymes, and found to have a profound impact on protein overall structure, function, and dynamics. Understanding the structure and dynamic behavior of the flap regions is crucial in the design of selective inhibitors against aspartic proteases. Cathepsin-D, an aspartic protease enzyme, has been implicated in a long list of degenerative diseases as well as breast cancer progression. Presented herein, for the first time, is a comprehensive description of the conformational flap dynamics of cathepsin-D using a comparative 50 ns "multiple" molecular dynamics simulations. Diverse collective metrics were proposed to accurately define flap dynamics. These are distance d1 between the flap tips residues (Gly79 and Met301); dihedral angle ϕ; in addition to TriCα angles Gly79-Asp33-Asp223, θ1 , and Gly79-Asp223-Met301, θ2 . The maximum distance attained throughout the simulation was 17.42 and 11.47 Å for apo and bound cathepsin-D, respectively, while the minimum distance observed was 8.75 and 6.32 Å for apo and bound cathepsin-D, respectively. The movement of the flap as well as the twist of the active pocket can properly be explained by measuring the angle, θ1 , between Gly79-Asp33-Met301 and correlating it with the distance Cα of the flap tip residues. The asymmetrical opening of the binding cavity was best described by the large shift of -6.26° to +20.94° in the dihedral angle, ϕ, corresponding to the full opening of the flap at a range of 31-33 ns. A wide-range of post-dynamic analyses was also applied in this report to supplement our findings. We believe that this report would augment current efforts in designing potent structure-based inhibitors against cathepsin-D in the treatment of breast cancer and other degenerative diseases. J. Cell. Biochem. 117: 2643-2657, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Methodsmentioning

confidence: 99%

Molecular Dynamics Simulations of Ligand‐Induced Flap Conformational Changes in Cathepsin‐D—A Comparative Study

Arodola

Soliman

2016

J of Cellular Biochemistry

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“…The objective of their research was to compare NMR driven flexibility with MD simulation ones (12). Also, there were a number of studies which have used a method called as the Multiple Molecular Dynamics Simulation (MMDS) (13)(14)(15)(16)(17). However, MD simulations will be repeated with exactly the same initial snapshots in this method, while the initial snapshots of the repeating MD simulations have some differences with each other in our method.…”

Section: Introductionmentioning

confidence: 99%

Variability of the Cyclin-Dependent Kinase 2 Flexibility Without Significant Change in the Initial Conformation of the Protein or Its Environment; a Computational Study

2016

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Protein flexibility probably is a phenomenon that can make the existence of the many protein conformations possible in contrast to a limited number. Many conformations in a protein are needed for doing many functions. For instance, based on searching IntAct PPI database with the UniprotKB accession number of hCDK2: P24941, hCDK2 has at least 200 different interactions with other proteins in addition to interactions by itself (1). As a structural characteristic, protein flexibility plays many functional roles with respect to different aspects of the proteins as well. Examples in this regard are enzyme catalysis and ligand-receptor interactions, substrate and ligand orientation, the turnover rate of the substrates, and reduction of the free energy barrier in the active sites (2).In structural bioinformatics tools, there are many instances regarding protein flexibility applications and usefulness; as an example, improvement of the small ligand-receptor docking (3,4 Background: Protein flexibility, which has been referred as a dynamic behavior has various roles in proteins' functions. Furthermore, for some developed tools in bioinformatics, such as protein-protein docking software, considering the protein flexibility, causes a higher degree of accuracy. Through undertaking the present work, we have accomplished the quantification plus analysis of the variations in the human Cyclin Dependent Kinase 2 (hCDK2) protein flexibility without affecting a significant change in its initial environment or the protein per se. Objectives:The main goal of the present research was to calculate variations in the flexibility for each residue of the hCDK2, analysis of their flexibility variations through clustering, and to investigate the functional aspects of the residues with high flexibility variations. Materials and Methods: Using Gromacs package (version 4.5.4), three independent molecular dynamics (MD) simulations of the hCDK2 protein (PDB ID: 1HCL) was accomplished with no significant changes in their initial environments, structures, or conformations, followed by Root Mean Square Fluctuations (RMSF) calculation of these MD trajectories. The amount of variations in these three curves of RMSF was calculated using two formulas.Results: More than 50% of the variation in the flexibility (the distance between the maximum and the minimum amount of the RMSF) was found at the region of Val-154. As well, there are other major flexibility fluctuations in other residues. These residues were mostly positioned in the vicinity of the functional residues. The subsequent works were done, as followed by clustering all hCDK2 residues into four groups considering the amount of their variability with respect to flexibility and their position in the RMSF curves. Conclusions:This work has introduced a new class of flexibility aspect of the proteins' residues. It could also help designing and engineering proteins, with introducing a new dynamic aspect of hCDK2, and accordingly, for the other similar globular proteins. In addition, it could provide a...

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Induced Mutation Proves a Potential Target for TB Therapy: A Molecular Dynamics Study on LprG

Machaba

Mhlongo

Soliman

2018

Cell Biochem Biophys

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Molecular dynamics (MD) simulations of wild-type and V91W mutant Mycobacterium tuberculosis-LprG (Mtb-LprG) were performed with the goal to provide a comprehensive understanding of the Mtb-LprG as a potential antimycobacterial target. A long-range MD simulations and post-MD analyzes led us to various results that plainly explained the impact of V91W mutation on Mtb-LprG. Herein, the results revealed that the wild-type is less stable compared to V91W mutant. This was further supported by root mean square fluctuation, where the V91W mutant showed a higher degree of flexibility compared to the wild-type. Dynamic cross-correlation analysis revealed that induced mutation leads to higher residual flexibility in the mutant structure as compared to the wild-type structure thus resulting in the existence of negatively correlated motions. The difference in principal component analysis scatter plot across the first two normal modes suggests a greater mobility of the V91W mutant conformation compared to the wild-type. Thermodynamic calculations revealed that the van der Waals (E) forces contribute the most towards binding free energy in a case of the V91W mutant as compared to the wild-type LprG complex. In addition, the residue interaction networks revealed more of E interaction existence among residues in case of the V91W mutant. This study supports the Mtb-LprG as a potential antimycobacterial target and also serves as a cornerstone to identifying new potential targets that have no inhibitors.

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Single Active Site Mutation Causes Serious Resistance of HIV Reverse Transcriptase to Lamivudine: Insight from Multiple Molecular Dynamics Simulations

Cited by 8 publications

References 71 publications

Molecular Dynamics Simulations of Ligand‐Induced Flap Conformational Changes in Cathepsin‐D—A Comparative Study

Molecular Dynamics Simulations of Ligand‐Induced Flap Conformational Changes in Cathepsin‐D—A Comparative Study

Variability of the Cyclin-Dependent Kinase 2 Flexibility Without Significant Change in the Initial Conformation of the Protein or Its Environment; a Computational Study

Induced Mutation Proves a Potential Target for TB Therapy: A Molecular Dynamics Study on LprG

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