4,248 research outputs found
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Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations.
Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein
Accelerating Electrostatic Surface Potential Calculation with Multiscale Approximation on Graphics Processing Units
Tools that compute and visualize biomolecular electrostatic surface potential have been used extensively for studying biomolecular function. However, determining the surface potential for large biomolecules on a typical desktop computer can take days or longer using currently available tools and methods. This paper demonstrates how one can take advantage of graphic processing units (GPUs) available in today’s typical desktop computer, together with a multiscale approximation method, to significantly speedup such computations. Specifically, the electrostatic potential computation, using an analytical linearized Poisson Boltzmann (ALPB) method, is implemented on an ATI Radeon 4870 GPU in combination with the hierarchical charge partitioning (HCP) multiscale approximation. This implementation delivers a combined 1800-fold speedup for a 476,040 atom viral capsid
Minimal Basis Iterative Stockholder: Atoms in Molecules for Force-Field Development
Atomic partial charges appear in the Coulomb term of many force-field models
and can be derived from electronic structure calculations with a myriad of
atoms-in-molecules (AIM) methods. More advanced models have also been proposed,
using the distributed nature of the electron cloud and atomic multipoles. In
this work, an electrostatic force field is defined through a concise
approximation of the electron density, for which the Coulomb interaction is
trivially evaluated. This approximate "pro-density" is expanded in a minimal
basis of atom-centered s-type Slater density functions, whose parameters are
optimized by minimizing the Kullback-Leibler divergence of the pro-density from
a reference electron density, e.g. obtained from an electronic structure
calculation. The proposed method, Minimal Basis Iterative Stockholder (MBIS),
is a variant of the Hirshfeld AIM method but it can also be used as a
density-fitting technique. An iterative algorithm to refine the pro-density is
easily implemented with a linear-scaling computational cost, enabling
applications to supramolecular systems. The benefits of the MBIS method are
demonstrated with systematic applications to molecular databases and extended
models of condensed phases. A comparison to 14 other AIM methods shows its
effectiveness when modeling electrostatic interactions. MBIS is also suitable
for rescaling atomic polarizabilities in the Tkatchenko-Sheffler scheme for
dispersion interactions.Comment: 61 pages, 12 figures, 2 table
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How Water's Properties Are Encoded in Its Molecular Structure and Energies.
How are water's material properties encoded within the structure of the water molecule? This is pertinent to understanding Earth's living systems, its materials, its geochemistry and geophysics, and a broad spectrum of its industrial chemistry. Water has distinctive liquid and solid properties: It is highly cohesive. It has volumetric anomalies-water's solid (ice) floats on its liquid; pressure can melt the solid rather than freezing the liquid; heating can shrink the liquid. It has more solid phases than other materials. Its supercooled liquid has divergent thermodynamic response functions. Its glassy state is neither fragile nor strong. Its component ions-hydroxide and protons-diffuse much faster than other ions. Aqueous solvation of ions or oils entails large entropies and heat capacities. We review how these properties are encoded within water's molecular structure and energies, as understood from theories, simulations, and experiments. Like simpler liquids, water molecules are nearly spherical and interact with each other through van der Waals forces. Unlike simpler liquids, water's orientation-dependent hydrogen bonding leads to open tetrahedral cage-like structuring that contributes to its remarkable volumetric and thermal properties
Toward transferable interatomic van der Waals interactions without electrons: The role of multipole electrostatics and many-body dispersion
We estimate polarizabilities of atoms in molecules without electron density,
using a Voronoi tesselation approach instead of conventional density
partitioning schemes. The resulting atomic dispersion coefficients are
calculated, as well as many-body dispersion effects on intermolecular potential
energies. We also estimate contributions from multipole electrostatics and
compare them to dispersion. We assess the performance of the resulting
intermolecular interaction model from dispersion and electrostatics for more
than 1,300 neutral and charged, small organic molecular dimers. Applications to
water clusters, the benzene crystal, the anti-cancer drug
ellipticine---intercalated between two Watson-Crick DNA base pairs, as well as
six macro-molecular host-guest complexes highlight the potential of this method
and help to identify points of future improvement. The mean absolute error made
by the combination of static electrostatics with many-body dispersion reduces
at larger distances, while it plateaus for two-body dispersion, in conflict
with the common assumption that the simple correction will yield proper
dissociative tails. Overall, the method achieves an accuracy well within
conventional molecular force fields while exhibiting a simple parametrization
protocol.Comment: 13 pages, 8 figure
Polarizable Water Model for the Coarse-Grained MARTINI Force Field
Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit or modeled explicitly as a van der Waals particle. The effect of polarization, and thus a proper screening of interactions depending on the local environment, is absent. Given the important role of water as a ubiquitous solvent in biological systems, its treatment is crucial to the properties derived from simulation studies. Here, we parameterize a polarizable coarse-grained water model to be used in combination with the CG MARTINI force field. Using a three-bead model to represent four water molecules, we show that the orientational polarizability of real water can be effectively accounted for. This has the consequence that the dielectric screening of bulk water is reproduced. At the same time, we parameterized our new water model such that bulk water density and oil/water partitioning data remain at the same level of accuracy as for the standard MARTINI force field. We apply the new model to two cases for which current CG force fields are inadequate. First, we address the transport of ions across a lipid membrane. The computed potential of mean force shows that the ions now naturally feel the change in dielectric medium when moving from the high dielectric aqueous phase toward the low dielectric membrane interior. In the second application we consider the electroporation process of both an oil slab and a lipid bilayer. The electrostatic field drives the formation of water filled pores in both cases, following a similar mechanism as seen with atomistically detailed models
Triblock copolyesters derived from lactic acid and glucose: synthesis, nanoparticle formation and simulation
ABA triblock copolyesters were synthesized by ring-opening polymerization (ROP) of l-lactide in solution initiated by a telechelic d-glucose-based polyester macroinitiator. The macroinitiator with a number-average molecular weight about 2500 g mol-1 was synthesized by non-stoichiometric polycondensation in the melt of 2,4:3,5-di-O-methylene-d-glucitol and dimethyl succinate. Two triblock copolyesters of Mn ranging between ~6000 and ~9000 g mol-1, and differing in the length of the polylactide blocks were prepared. These copolyesters started to decompose when heated at ~220 °C and degraded slowly upon aqueous incubation under physiological conditions. They did not display any perceivable crystallinity and showed a single glass transition temperature (Tg) around 60 °C with the higher value corresponding to the larger content in glucitol units. The copolyesters were able to form nanoparticles with average diameters of ~100–130 nm and satisfactory dispersity. The effect of the block lengths on size, ¿-potential values and physical stability of the nanoparticles was evaluated. A molecular dynamics simulation study allowed modelling the two-phase structure of the nanoparticles and evidenced the preference of the glucose-based block to be peripherally located.Peer ReviewedPostprint (author's final draft
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