scholarly journals Computational Insights Into Avidity of Polymeric Multivalent Binders

2019 ◽  
Author(s):  
E Zumbro ◽  
J Witten ◽  
A Alexander-Katz

AbstractMultivalent binding interactions are commonly found throughout biology to enhance weak monovalent binding such as between glycoligands and protein receptors. Designing multivalent polymers to bind to viruses and toxic proteins is a promising avenue for inhibiting their attachment and subsequent infection of cells. Several studies have focused on oligomeric multivalent inhibitors and how changing parameters such as ligand shape and size, and linker length and flexibility affect binding. However, experimental studies of how larger structural parameters of multivalent polymers such as degree of polymerization affect binding avidity to targets have mixed results with some finding an improvement with longer polymers and some finding no effect. Here, we use Brownian dynamics simulations to provide a theoretical understanding of how degree of polymerization affects the binding avidity of multivalent polymers. We show that longer polymers increase binding avidity to multivalent targets, but reach a limit in binding avidity at high degrees of polymerization. We also show that when interacting with multiple targets simultaneously, longer polymers are able to use inter-target interactions to promote clustering and improve binding efficiency. We expect our results to narrow the design space for optimizing the structure and effectiveness of multivalent inhibitors, as well as be useful to understand biological design strategies for multivalent binding.

Author(s):  
Amit Gupta ◽  
Xuan Wu ◽  
Ranganathan Kumar

This study discusses the merits of various physical mechanisms that are responsible for enhancing the heat transfer in nanofluids. Experimental studies have cemented the claim that ‘seeding’ liquids with nanoparticles can increase the thermal conductivity of the nanofluid by up to 40% for metallic and oxide nanoparticles dispersed in a base liquid. Experiments have also shown that the rise in conductivity of the nanofluid is highly dependent on the size and concentration of the nanoparticles. On the theoretical side, traditional models like Maxwell or Hamilton-Crosser models cannot explain this unusually high heat transfer. Several mechanisms have been postulated in the literature such as Brownian motion, thermal diffusion in nanoparticles and thermal interaction of nanoparticles with the surrounding fluid, the formation of an ordered liquid layer on the surface of the nanoparticle and microconvection. This study concentrates on 3 possible mechanisms: Brownian dynamics, microconvection and lattice vibration of nanoparticles in the fluid. By considering two nanofluids, copper particles dispersed in ethylene glycol, and silica in water, it is determined that translational Brownian motion of the nanoparticles, presence of an interparticle potential and the microconvection heat transfer are mechanisms that play only a smaller role in the enhancement of thermal conductivity. On the other hand, the lattice vibrations, determined by molecular dynamics simulations show a great deal of promise in increasing the thermal conductivity by as much as 23%. In a simplistic sense, the lattice vibration can be regarded as a means to simulate the phononic transport from solid to liquid at the interface.


2018 ◽  
Author(s):  
Benjamin R. Jagger ◽  
Christoper T. Lee ◽  
Rommie Amaro

<p>The ranking of small molecule binders by their kinetic (kon and koff) and thermodynamic (delta G) properties can be a valuable metric for lead selection and optimization in a drug discovery campaign, as these quantities are often indicators of in vivo efficacy. Efficient and accurate predictions of these quantities can aid the in drug discovery effort, acting as a screening step. We have previously described a hybrid molecular dynamics, Brownian dynamics, and milestoning model, Simulation Enabled Estimation of Kinetic Rates (SEEKR), that can predict kon’s, koff’s, and G’s. Here we demonstrate the effectiveness of this approach for ranking a series of seven small molecule compounds for the model system, -cyclodextrin, based on predicted kon’s and koff’s. We compare our results using SEEKR to experimentally determined rates as well as rates calculated using long-timescale molecular dynamics simulations and show that SEEKR can effectively rank the compounds by koff and G with reduced computational cost. We also provide a discussion of convergence properties and sensitivities of calculations with SEEKR to establish “best practices” for its future use.</p>


Author(s):  
Konstantinos Manikas ◽  
Markus Hütter ◽  
Patrick D. Anderson

AbstractThe effect of time-dependent external fields on the structures formed by particles with induced dipoles dispersed in a viscous fluid is investigated by means of Brownian Dynamics simulations. The physical effects accounted for are thermal fluctuations, dipole-dipole and excluded volume interactions. The emerging structures are characterised in terms of particle clusters (orientation, size, anisotropy and percolation) and network structure. The strength of the external field is increased in one direction and then kept constant for a certain amount of time, with the structure formation being influenced by the slope of the field-strength increase. This effect can be partially rationalized by inhomogeneous time re-scaling with respect to the field strength, however, the presence of thermal fluctuations makes the scaling at low field strength inappropriate. After the re-scaling, one can observe that the lower the slope of the field increase, the more network-like and the thicker the structure is. In the second part of the study the field is also rotated instantaneously by a certain angle, and the effect of this transition on the structure is studied. For small rotation angles ($$\theta \le 20^{{\circ }}$$ θ ≤ 20 ∘ ) the clusters rotate but stay largely intact, while for large rotation angles ($$\theta \ge 80^{{\circ }}$$ θ ≥ 80 ∘ ) the structure disintegrates and then reforms, due to the nature of the interactions (parallel dipoles with perpendicular inter-particle vector repel each other). For intermediate angles ($$20<\theta <80^{{\circ }}$$ 20 < θ < 80 ∘ ), it seems that, during rotation, the structure is altered towards a more network-like state, as a result of cluster fusion (larger clusters). The details provided in this paper concern an electric field, however, all results can be projected into the case of a magnetic field and paramagnetic particles.


2021 ◽  
Author(s):  
Dillip Kumar Mohapatra ◽  
Philip James Camp ◽  
John Philip

We probe the influence of particle size polydispersity on field-induced structures and structural transitions in magnetic fluids (ferrofluids) using phase contrast optical microscopy, light scattering and Brownian dynamics simulations. Three...


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Renu Wadhwa ◽  
Neetu Singh Yadav ◽  
Shashank P. Katiyar ◽  
Tomoko Yaguchi ◽  
Chohee Lee ◽  
...  

AbstractPoor bioavailability due to the inability to cross the cell membrane is one of the major reasons for the failure of a drug in clinical trials. We have used molecular dynamics simulations to predict the membrane permeability of natural drugs—withanolides (withaferin-A and withanone) that have similar structures but remarkably differ in their cytotoxicity. We found that whereas withaferin-A, could proficiently transverse through the model membrane, withanone showed weak permeability. The free energy profiles for the interaction of withanolides with the model bilayer membrane revealed that whereas the polar head group of the membrane caused high resistance for the passage of withanone, the interior of the membrane behaves similarly for both withanolides. The solvation analysis further revealed that the high solvation of terminal O5 oxygen of withaferin-A was the major driving force for its high permeability; it interacted with the phosphate group of the membrane that led to its smooth passage across the bilayer. The computational predictions were tested by raising and recruiting unique antibodies that react to withaferin-A and withanone. The time-lapsed analyses of control and treated cells demonstrated higher permeation of withaferin-A as compared to withanone. The concurrence between the computation and experimental results thus re-emphasised the use of computational methods for predicting permeability and hence bioavailability of natural drug compounds in the drug development process.


Author(s):  
Oliver Henrich ◽  
Fabian Weysser ◽  
Michael E. Cates ◽  
Matthias Fuchs

Brownian dynamics simulations of bidisperse hard discs moving in two dimensions in a given steady and homogeneous shear flow are presented close to and above the glass transition density. The stationary structure functions and stresses of shear-melted glass are compared quantitatively to parameter-free numerical calculations of monodisperse hard discs using mode coupling theory within the integration through transients framework. Theory qualitatively explains the properties of the yielding glass but quantitatively overestimates the shear-driven stresses and structural anisotropies.


1981 ◽  
Vol 21 (06) ◽  
pp. 747-762 ◽  
Author(s):  
Karl E. Bennett ◽  
Craig H.K. Phelps ◽  
H. Ted Davis ◽  
L.E. Scriven

Abstract The phase behavior of microemulsions of brine, hydrocarbon, alcohol, and a pure alkyl aryl sulfonate-sodium 4-(1-heptylnonyl) benzenesulfonate (SHBS or Texas 1) was investigated as a function of the concentration of salt (NaCl, MgCl2, or CaCl2), the hydrocarbon (n-alkanes, octane to hexadecane), the alcohol (butyl and amyl isomers), the concentration of surfactant, and temperature. The phase behavior mimics that of similar systems with the commercial surfactant Witco TRS 10–80. The phase volumes follow published trends, though with exceptions.A mathematical framework is presented for modeling phase behavior in a manner consistent with the thermodynamically required critical tie lines and plait point progressions from the critical endpoints. Hand's scheme for modeling binodals and Pope and Nelson's approach to modeling the evolution of the surfactant-rich third phase are extended to satisfy these requirements.An examination of model-generated progressions of ternary phase diagrams enhances understanding of the experimental data and reveals correlations of relative phase volumes (volume uptakes) with location of the mixing point (overall composition) relative to the height of the three-phase region and the locations of the critical tie lines (critical endpoints and conjugate phases). The correlations account, on thermodynamic grounds, for cases in which the surfactant is present in more than one phase or the phase volumes change discontinuously, both cases being observed in the experimental study. Introduction The phase behavior of a surfactant-based micellar formulation is one of the major factors governing the displacement efficiency of any chemical flooding process employing that formulation. Knowledge of phase behavior is, thus, important for the interpretation of laboratory core floods, the design of flooding processes, and the evaluation of field tests. Phase behavior is connected intimately with other determinants of the flooding process, such as interfacial tension and viscosity. Since the number of equilibrium phases and their volumes and appearances are easier to measure and observe than phase compositions, viscosities, and interfacial tensions, there is great interest in understanding the phase-volume/phase-property relationships. Commercial surfactants, such as Witco TRS 10-80, are sulfonates of crude or partially refined oil. While they seem to be the most economically practicable surfactants for micellar flooding, their behavior, particularly with crude oils and reservoir brines, can be difficult to interpret, the phases varying with time and from batch to batch. Phase behavior studies with a small number of components, in conjunction with a theoretical understanding of phase behavior progressions, can aid in understanding more complex behavior. In particular, one can begin to appreciate which seemingly abnormal experimental observations (e.g., surfactant present in more than one phase or a discontinuity in phase volume trends) are merely features of certain regions of any phase diagram and which are peculiar to the specific crude oil or commercial surfactant used in the study.We report here experimental studies of the phase behavior of microemulsions of a pure sulfonate surfactant (Texas 1), a single normal alkane hydrocarbon, a simple brine, and a small amount of a suitable alcohol as cosurfactant or cosolvent. The controlled variables are hydrocarbon chain length, alcohol, salinity, salt type (NaCl, MgCl2, or CaCl2), surfactant purity, surfactant concentration, and temperature. Many of these experimental data were presented earlier. SPEJ P. 747^


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