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Papers by Anjela Manandhar

Research paper thumbnail of The interaction of supramolecular anticancer drug amphiphiles with phospholipid membranes

Nanoscale Advances, 2021

Molecular dynamics simulations probe drug delivery vehicle-membrane interaction.

Research paper thumbnail of Sequence Dependent Barriers to Nucleosome Unwrapping

Sequence Dependent Barriers to Nucleosome Unwrapping

Biophysical Journal, 2021

Research paper thumbnail of Rational Coarse-Grained Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes

The Journal of Physical Chemistry B, 2019

Peptide self-assembly has been used to design an array of nanostructures that possess functional ... more Peptide self-assembly has been used to design an array of nanostructures that possess functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). These DAs have shown to possess an inherently high drug loading with a tunable release mechanism. Herein we report rational coarse grained molecular dynamics simulations of the self-assembly process and the structure and stability of pre-assembled nanotubes at longer time scales (s). We find aggregation between these DAs is at the sub-microsecond time scale is driven by directional aromatic interactions between the drugs. The drugs form a large and high-density nucleus that is stable throughout microsecond time scales. Simulations of nanotubes characterize the drug-drug stacking and find correlations at nm length-scales. These simulations can inform the rational molecular design of drug amphiphiles.

Research paper thumbnail of Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers

The journal of physical chemistry. B, Jan 6, 2018

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule ... more At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the β subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer. We perform multiple replicas of long-time atomistic MD simulations (3 replicas, 0.3 μs for each replica, 0.9 μs for each octamer system, and 1.8 μs total) of both octamers. We observe that a single GTP cap layer induces structural differences in neighboring PFs, finding that one PF possesses a gradual curvature, compared to the second PF which possesses a kinked conformation. This results in either curling or splaying between these ...

Research paper thumbnail of Molecular simulations of peptide amphiphiles

Org. Biomol. Chem., 2017

This review describes recent progress in the area of molecular simulations of peptide assemblies,... more This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles, and drug-amphiphiles.

Research paper thumbnail of Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening

Journal of Chemical Information and Modeling, 2021

Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (... more Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2). This highly pathogenic virus has to date caused >71 million infections and >1.6 million deaths in >180 countries. Several vaccines and drugs are being studied as possible treatments or prophylactics of this viral infection. M3CLpro (coronavirus main cysteine protease) is a promising drug target as it has a significant role in viral replication. Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding. The binding free energy was calculated for water molecules at different locations of the binding site, and molecular dynamics (MD) simulations were carried out for the M3CLpro/boceprevir complex, to thoroughly understand the chemical environment of the binding site. Several HCV NS3/4a protease inhibitors were tested in vitro against M3CLpro. Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic.

Research paper thumbnail of Redetermination and absolute configuration of (+)-7-epiclusianone

Acta Crystallographica Section E Structure Reports Online, 2012

Research paper thumbnail of The interaction of supramolecular anticancer drug amphiphiles with phospholipid membranes

Nanoscale Advances, 2021

Molecular dynamics simulations probe drug delivery vehicle-membrane interaction.

Research paper thumbnail of Sequence Dependent Barriers to Nucleosome Unwrapping

Sequence Dependent Barriers to Nucleosome Unwrapping

Biophysical Journal, 2021

Research paper thumbnail of Rational Coarse-Grained Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes

The Journal of Physical Chemistry B, 2019

Peptide self-assembly has been used to design an array of nanostructures that possess functional ... more Peptide self-assembly has been used to design an array of nanostructures that possess functional biomedical applications. Experimental studies have reported nanofilament and nanotube formation from peptide-based drug amphiphiles (DAs). These DAs have shown to possess an inherently high drug loading with a tunable release mechanism. Herein we report rational coarse grained molecular dynamics simulations of the self-assembly process and the structure and stability of pre-assembled nanotubes at longer time scales (s). We find aggregation between these DAs is at the sub-microsecond time scale is driven by directional aromatic interactions between the drugs. The drugs form a large and high-density nucleus that is stable throughout microsecond time scales. Simulations of nanotubes characterize the drug-drug stacking and find correlations at nm length-scales. These simulations can inform the rational molecular design of drug amphiphiles.

Research paper thumbnail of Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers

The journal of physical chemistry. B, Jan 6, 2018

At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule ... more At the molecular level, the dynamic instability (random growth and shrinkage) of the microtubule (MT) is driven by the nucleotide state (GTP vs GDP) in the β subunit of the tubulin dimers at the MT cap. Here, we use large-scale molecular dynamics (MD) simulations and normal-mode analysis (NMA) to characterize the effect of a single GTP cap layer on tubulin octamers composed of two neighboring protofilaments (PFs). We utilize recently reported high-resolution structures of dynamic MTs to simulate a GDP octamer both with and without a single GTP cap layer. We perform multiple replicas of long-time atomistic MD simulations (3 replicas, 0.3 μs for each replica, 0.9 μs for each octamer system, and 1.8 μs total) of both octamers. We observe that a single GTP cap layer induces structural differences in neighboring PFs, finding that one PF possesses a gradual curvature, compared to the second PF which possesses a kinked conformation. This results in either curling or splaying between these ...

Research paper thumbnail of Molecular simulations of peptide amphiphiles

Org. Biomol. Chem., 2017

This review describes recent progress in the area of molecular simulations of peptide assemblies,... more This review describes recent progress in the area of molecular simulations of peptide assemblies, including peptide-amphiphiles, and drug-amphiphiles.

Research paper thumbnail of Targeting SARS-CoV-2 M3CLpro by HCV NS3/4a Inhibitors: In Silico Modeling and In Vitro Screening

Journal of Chemical Information and Modeling, 2021

Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (... more Currently the entire human population is in the midst of a global pandemic caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2). This highly pathogenic virus has to date caused >71 million infections and >1.6 million deaths in >180 countries. Several vaccines and drugs are being studied as possible treatments or prophylactics of this viral infection. M3CLpro (coronavirus main cysteine protease) is a promising drug target as it has a significant role in viral replication. Here we use the X-ray crystal structure of M3CLpro in complex with boceprevir to study the dynamic changes of the protease upon ligand binding. The binding free energy was calculated for water molecules at different locations of the binding site, and molecular dynamics (MD) simulations were carried out for the M3CLpro/boceprevir complex, to thoroughly understand the chemical environment of the binding site. Several HCV NS3/4a protease inhibitors were tested in vitro against M3CLpro. Specifically, asunaprevir, narlaprevir, paritaprevir, simeprevir, and telaprevir all showed inhibitory effects on M3CLpro. Molecular docking and MD simulations were then performed to investigate the effects of these ligands on M3CLpro and to provide insights into the chemical environment of the ligand binding site. Our findings and observations are offered to help guide the design of possible potent protease inhibitors and aid in coping with the COVID-19 pandemic.

Research paper thumbnail of Redetermination and absolute configuration of (+)-7-epiclusianone

Acta Crystallographica Section E Structure Reports Online, 2012