5 research outputs found
Molecular Simulation of the Concentration-Dependent Interaction of Hydrophobic Drugs with Model Cellular Membranes
We report here the interactions between
a hydrophobic drug and
a model cellular membrane at the molecular level using all-atom molecular
dynamics simulations of paclitaxel, a hydrophobic cancer drug. The
calculated free energy of a single drug across the bilayer interface
displays a minimum in the outer hydrophobic zone of the membrane.
The transfer free energy shows excellent agreement with reported experimental
data. In two sets of long-time simulations of high concentrations
of drug in the membrane (12 and 11 mol %), the drugs display substantial
clustering and rotation with significant directional preference in
their diffusion. The main taxane ring partitions in the outer hydrophobic
zone, while the three phenyl rings prefer to be closer to the hydrophobic
core of the membrane. The clustering of the drug molecules, order
parameters of the lipid tails, and water penetration suggest that
the fluidity and permeability of the membrane are affected by the
concentration of drugs that it contains. Furthermore, at the high-concentration
limit, the free energy minimum shifts closer to the hydrophobic core
and the central barrier to cross the membrane decreases. Moreover,
the transfer free energy change substantially increases, suggesting
that increasing concentration facilitates drug partitioning into the
membrane
Molecular Dynamics Simulations of Supramolecular Anticancer Nanotubes
We
report here on long-time all-atomistic molecular dynamics simulations
of functional supramolecular nanotubes composed by the self-assembly
of peptide-drug amphiphiles (DAs). These DAs have been shown to possess
an inherently high drug loading of the hydrophobic anticancer drug
camptothecin. We probe the self-assembly mechanism from random with
∼0.4 μs molecular dynamics simulations. Furthermore,
we also computationally characterize the interfacial structure, directionality
of π–π stacking, and water dynamics within several
peptide-drug nanotubes with diameters consistent with the reported
experimental nanotube diameter. Insight gained should inform the future
design of these novel anticancer drug delivery systems
π–π Stacking Mediated Chirality in Functional Supramolecular Filaments
While a great diversity of peptide-based
supramolecular filaments
have been reported, the impact of an auxiliary segment on the chiral
assembly of peptides remains poorly understood. Herein we report on
the formation of chiral filaments by the self-assembly of a peptide-drug
conjugate containing an aromatic drug camptothecin (CPT) in a computational
study. We find that the chirality of the filament is mediated by the
π–π stacking between CPTs, not only by the well-expected
intermolecular hydrogen bonding between peptide segments. Our simulations
show that π–π stacking of CPTs governs the early
stages of the self-assembly process, while a hydrogen bonding network
starts at a relatively later stage to contribute to the eventual morphology
of the filament. Our results also show the possible presence of water
within the core of the CPT filament. These results provide very useful
guiding principles for the rational design of supramolecular assemblies
of peptide conjugates with aromatic segments
Mechanistic Insights into Phosphopeptide–BRCT Domain Association: Preorganization, Flexibility, and Phosphate Recognition
Promiscuous proteins are commonly observed in biological
systems,
for example, in modular domains that recognize phosphopeptides during
signal transduction. This promiscuous recognition is of fundamental
interest in chemistry and biology but is challenging when designing
phosphopeptides <i>in silico</i> for cell biology studies.
To investigate promiscuous recognition and binding processes of phosphopeptides
and the modular domain, we selected a domain essential in breast cancerî—¸the
breast-cancer–associated protein 1 (BRCA1) C-terminal (BRCT)
repeats as our model system. We performed molecular dynamics simulations
and detailed analyses of the dihedral space to study protein fluctuation
and conformational changes with phosphopeptide binding. We also studied
the association processes of phosphorylated and unphosphorylated peptides
using Brownian dynamics with a coarse-grained model. We found that
the BRCT domain is preorganized for phosphopeptide binding but has
a moderate arrangement of side chains to form complexes with various
types of phosphopeptides. Phosphopeptide binding restricts the system
motion in general, while the nonpolar phosphopeptide becomes more
flexible in the bound state. Our analysis found that the BRCT domain
utilizes different mechanisms, usually termed lock and key, induced-fit,
and population-shift/conformational-selection models, to recognize
peptides with different features. Brownian dynamics simulations revealed
that the charged phosphate group may not always accelerate peptide
association processes, but it helps the phosphopeptide orient into
binding pockets accurately and stabilizes the complex. This work provides
insights into molecular recognition in the promiscuous protein system
Effect of Nucleotide State on the Protofilament Conformation of Tubulin Octamers
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 PFs. We suggest
that this is due to asymmetric strengths of longitudinal contacts
between the two PFs. Furthermore, using NMA, we calculate mechanical
properties of these octamer systems and find that octamer system with
a single GTP cap layer possesses a lower flexural rigidity