Search

Molecular dynamics simulations have been performed on a complex in which clusters of boron in the form of molecules of the nanodiamond ortho-carborane (C2B10H12) have been inserted into the four large nonpolar cavities of a nanotube of the right-handed coiled-coil (RHCC)tetrabrachion. The techniques of multi-configurational thermodynamic integration, steered molecular dynamics and umbrella sampling have been combined to investigate the energetics of storage of ortho-carborane in the cavities and to map out the free energy landscape of the RHCC-tetrabrachion-ortho-carboranecomplex along the central channel and along directions transverse to the central channel. The purpose of the study was to explore potential pathways for the diffusion of ortho-carborane between the cavities and the solvent and to assess the stability of the complex as a possible drug delivery system for boron neutron capture therapy (BNCT). The investigation reveals a complex free energy landscape with a multitude of peaks and valleys, all of which can be related to specific architectural elements of the RHCC-nanotube, and the activation barriers for ortho-carborane capture and release support the requirements for rapid cargo uptake coupled with tight binding to the cavities.

This study reports the results of binding free energy calculations for CB[8] host-guest systems in the SAMPL6 blind challenge (receipt ID 3z83m). Force-field parameters were developed specific for each of host and guest molecules to improve configurational sampling. We used quantum mechanical (QM) implicit solvent calculations and QM force matching to determine non-bonded (partial atomic charges) and bonded terms, respectively. Free energy calculations were carried out using the double-decoupling method (DDM) combined with Hamiltonian replica exchange method (HREM) and Bennett acceptance ratio (BAR) method. The root mean square error (RMSE) of the predicted values using DDM with respect to the experimental results was 4.32 kcal/mol. The coefficient of determination (R2) and Kendall rank coefficient (τ) were 0.49 and 0.52, respectively, highest of all submissions. In addition, these were compared to the results obtained by umbrella sampling (US) and weighted histogram analysis method (WHAM). Overall, DDM achieved a higher prediction accuracy than the US method. Results are discussed in terms of parameterization and free energy simulations. [ABSTRACT FROM AUTHOR]

Molecular dynamics simulations have been performed on a complex in which clusters of boron in the form of molecules of the nanodiamond ortho -carborane ( C 2 B 10 H 12 ) have been inserted into the four large nonpolar cavities of a nanotube of the right-handed coiled-coil ( R H C C ) t e t r a b r a c h i o n . The techniques of multi-configurational thermodynamic integration, steered molecular dynamics and umbrella sampling have been combined to investigate the energetics of storage of ortho -carborane in the cavities and to map out the free energy landscape of the RHCC - t e t r a b r a c h i o n - o r t h o - c a r b o r a n e complex along the central channel and along directions transverse to the central channel. The purpose of the study was to explore potential pathways for the diffusion of ortho -carborane between the cavities and the solvent and to assess the stability of the complex as a possible drug delivery system for boron neutron capture therapy (BNCT). The investigation reveals a complex free energy landscape with a multitude of peaks and valleys, all of which can be related to specific architectural elements of the RHCC - n a n o t u b e , and the activation barriers for ortho -carborane capture and release support the requirements for rapid cargo uptake coupled with tight binding to the cavities., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2021 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)

Tetrabrachion forms the key component of the S-layer of Staphylothermus marinus. Molecular dynamics simulations have been used to study the energetics of occupancy of cavity 3 of the right-handed coiled-coil stalk of tetrabrachion by both water molecules and cyclooctasulfur S 8 crowns, as well as to determine possible pathways and free energy barriers for the diffusion of both water and cyclooctasulfur through the peptide walls of RHCC tetrabrachion between cavity 3 and bulk solvent. Calculations of the transfer free energy from solvent to cavity show that clusters of six, seven and eight water molecules are marginally stable in cavity 3, but that occupancy of the cavity by a cyclooctasulfur ring is favoured significantly over water clusters of all sizes. Thermal activation simulations at T  = 400 K revealed that water molecules diffusing through the wall pass through a sequence of metastable configurations where they are temporarily immobilized by forming networks of hydrogen bonds with specific wall residues. Calculations of the free energy of these metastable configurations using multi-configurational thermodynamic integration yielded a free energy profile with a principal free energy maximum ∆G ~50 kJ / mol and a slight activation asymmetry in favour of the direction from cavity to solvent. Potential exit pathways for cyclooctasulfur were investigated with the methods of steered molecular dynamics and umbrella sampling. The cyclooctasulfur was steered through a gap in the tetrabrachion wall along a linear path from cavity 3 into the solvent and the resulting trajectory was subdivided into 22 sampling windows. The free energy profile created for the trajectory by umbrella sampling showed a sharp principal maximum as a function of the reaction coordinate with asymmetric free energy barriers ∆G exit ~220 kJ / mol and ∆G entrance ~100 kJ / mol for cavity exit and entrance, respectively.