Thermodynamics and Kinetics of Drug Binding, Volume 65
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The resulting spectra in Fig. Quite interestingly, out of the 4 considered arrangements I-IV , only the antiparallel dimer labeled as II yielded spectra that — although shifted — are in qualitative agreement with the experimental data here taken from a recent work by Starzyk et al.
This suggests that in higher-order oligomers, this particular arrangement of neighboring monomers can be prevailing due to a thermodynamic selection. However, the CD signal intensities of the dimers, albeit higher than in case of monomers, do not account for the enhancement of intensity observed in the spectroscopic studies, indicating that the structures observed experimentally could be higher oligomers or polymolecular aggregates of asymmetric structure, rather than sole dimers.
The vertical lines correspond to individual excitations, which were convolved with a Gaussian function to simulate the continuous spectrum solid line. Intensities are normalized to correspond to a single AmB molecule, and scaled to reflect the relative populations of dimer geometries. The gray dashed line corresponds to the experimental CD signal, taken from a recent study by Starzyk et al. Tetramers were chosen as model intermediates of further oligomerization based on recent suggestions concerning their possible relevance for the channel-forming activity of AmB 29 , It should be noted here that the enormous configuration space available for tetramers cannot be sampled adequately with relatively short equilibrium simulations, which allows only for a qualitative discussion of the behavior of oligomers.
S4 , no clear propensity for a particular arrangement — either parallel or antiparallel — could be observed. This indicates a lack of clear selection of the structures that yielded experimental-like CD signals in the dimeric form. Moreover, in the concentration of AmB used in our simulations ca.
Since we observed no preference for a particular arrangement, and given that parallel and antiparallel dimer geometries are roughly equiprobable, our results suggest that AmB molecules in higher oligomers, such as tetramers, align in parallel and antiparallel manner with roughly equal probability. Finally, it is worth noting that the solvent-exposed hydrophobic surface of dimers and tetramers is virtually the same ca.
S2B and Fig. C Overall and hydrophobic solvent accessible surface area of AmB tetramers, in each case averaged over 6 trajectories of the parallel-antiparallel p-a , parallel-parallel p-p and antiparallel-antiparallel a-a dimer pairs. E Large hydrophobic patches on the surface of AmB tetramers indicate their high propensity to higher-order aggregation.
In the present work, we used molecular dynamics simulations to study the association of AmB molecules in an aqueous environment. Our free energy calculations indicate that dimers begin to form already in the therapeutic, sub-micromolar concentrations, and that their formation is a barrierless, diffusion-controlled process. While AmB dimers turn out to be flexible and dynamic — with a sub-microsecond parallel-antiparallel flipping rate — the formation of tetramers significantly inhibited large structural rearrangements within the oligomer.
Moreover, the results of circular dichroism quantum chemical calculations reveal that individual stable dimer geometries yield quite different signature signals, but the resulting spectrum, when compared with that of a monomer, does not account for the spectral shift observed experimentally.
This suggests that the shift, used to experimentally pinpoint the onset of oligomerization, results from the formation of higher oligomers, and not dimers alone. As evidenced by previous studies, the selectivity of AmB depends on the oligomeric state of drug molecules: at low concentrations, when only AmB monomers exist in solution, the drug has a greater tendency to enter ergosterol-rich fungal membranes, while cholesterol-rich mammalian membranes remained impenetrable until higher drug concentrations.
It is therefore plausible that the selectivity of the drug stems from the presence of monomers, and oligomerization abolishes the distinction between fungal and mammalian membranes and leads to the toxic side effects of AmB. Our results indicate that this dependence can partially stem from a large hydrophobic solvent-accessible surface area SASA of AmB oligomers: despite the laterally amphiphilic character of AmB hydrophobic polyene and hydrophilic polyol chains , dimers and tetramers retained large hydrophobic SASA upon association.
We also note that the quick interconversion between individual arrangements of dimers, with several roughly equiprobable stable geometries, can additionally facilitate the passage of dimers through a complex membrane-water interface. We performed a series of molecular dynamics simulations of two amphotericin B molecules in an aqueous environment. All energy minimizations and molecular dynamics simulations of dimers were performed using NAMD Simulations of pairs of dimers were performed in Gromacs 35 , using the same set of force field and run parameters.
Dimers were placed in a 6. Pairs of dimers were placed in a cubic box of 6. Particle-mesh Ewald summation 37 was used to calculate long-range electrostatic interactions, and the corresponding short-range part was computed with a direct-space cutoff of 1. The Lennard-Jones potential and forces were smoothly switched off between 1. For the antibiotic molecule, the same parameter set was used as in the number of previous studies 17 , 40 , AmB molecules were in the zwitterionic form, i. In our simulations, we divided the interval 4.
The initial structures of stable AmB dimers were taken from a recent study Pairs of dimers were placed in an orthogonal configuration in such a way that the PBC images in the XY plane were equally spaced. For each possible pair of dimers parallel-parallel, parallel-antiparallel, antiparallel-antiparallel , six ns equilibrium trajectories were generated, starting from different initial configurations, yielding a total simulation time of 7.
For the circular dichroism CD calculations, representative structures were extracted from the umbrella sampling trajectories. From each minimum labeled as I-IV in Fig. Electronic circular dichroism spectra were calculated for each structure using the TD-DFT method as implemented in the Gaussian software The polarizable continuum model PCM was used to account for the aqueous environment.
The on-rate was obtained as a solution to the steady-state Smoluchowski equation from the following formula 48 :. The values of the coefficient were interpolated at intermediate distances, and extrapolated beyond the sampled interval as a constant. In the model, the apparent relaxation time was calculated as the autocorrelation time for the second Legendre polynomial of the cosine of the angle formed by two monomers, and the sigma parameter was obtained by fitting a gaussian function to the entropy-corrected angular distribution.
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Systematic exploration of multiple drug binding sites
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Free energy of binding between the drug and its membrane targets. Recent progress in the study of the interactions of amphotericin B with cholesterol and ergosterol in lipid environments. Effect of cholesterol and ergosterol on the antibiotic amphotericin B interactions with dipalmitoylphosphatidylcholine monolayers: X-ray reflectivity study. Acta , doi: Matsumori, N.
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Amphotericin B covalent dimers forming sterol-dependent ion-permeable membrane channels. Yamaji, N. One-sided action of amphotericin B on cholesterol-containing membranes is determined by its self-association in the medium.
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Gruszecki, W. Dimers of polyene antibiotic amphotericin B detected by means of fluorescence spectroscopy: Molecular organization in solution and in lipid membranes. Spectroscopic studies of molecular organization of antibiotic amphotericin B in monolayers and dipalmitoylphosphatidylcholine lipid multibilayers. Starzyk, J. B , — Molecular dynamics of amphotericin B. Dimer in water. Balakrishnan, A. Clejan, S. Rates of amphotericin B and filipin association with sterols. A study of changes in sterol structure and phospholipid composition of vesicles.
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Phillips, J. Scalable molecular dynamics with NAMD. Pronk, S. Bioinformatics 29 , — Feller, S. Constant pressure molecular dynamics simulation: The Langevin piston method.
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The method. Frisch, M. Gaussian 09, Revision A. Jeremy D. Cheeseman, Andrew D. Corbett, James L. Gleason, Romas J Kazlauskas. Current drug discovery using combinatorial chemistry involves synthesis followed by screening, but emerging methods involve receptor-assistance to combine these steps.
Adding stoichiometric amounts of receptor during library synthesis alters the kinetics or thermodynamics of the synthesis in a way that identifies the best-binding library members. Three main methods have emerged thus far in receptor-assisted combinatorial chemistry: dynamic combinatorial libraries, receptor-accelerated synthesis, and a new method, pseudo-dynamic libraries. Pseudo-dynamic libraries apply both thermodynamics and kinetics to amplify library members to easily observable levels, and attain selectivity heretofore unseen in receptor-assisted systems.
Receptor-assisted combinatorial chemistry : Thermodynamics and kinetics in drug discovery. N2 - Current drug discovery using combinatorial chemistry involves synthesis followed by screening, but emerging methods involve receptor-assistance to combine these steps. AB - Current drug discovery using combinatorial chemistry involves synthesis followed by screening, but emerging methods involve receptor-assistance to combine these steps. Receptor-assisted combinatorial chemistry Thermodynamics and kinetics in drug discovery. Biotechnology Institute.