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Graphical abstract 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. 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., 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.

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 S8 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 = 400K 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 ∆Gexit~220 kJ/mol and ∆Gentrance~100 kJ/mol for cavity exit and entrance, respectively., Graphical Abstract Unlabelled Image

There have been many recent articles in this journal highlighting simple demonstrations of a wide variety of acoustic phenomena. In introductory physics courses, sound waves and their propagation through air, and resonance in musical instruments, are covered in detail. However, attention is not usually paid to the active role that our ears play in transforming sound waves to create various types of combination tones. Furthermore, many physics textbooks mention that pitch is related to frequency, but do not elaborate on the specifics of the relationship. Teaching the physics behind combination tones allows for an excellent application of physics to biology, and is also an interesting way of exploring the relationship between frequency and pitch. In the first part of the paper, the physics of human hearing and the theory behind combination tones is introduced. In the second part of the paper, demonstrations are outlined and the results are presented.

Polycyclic aromatic hydrocarbons (PAHs) are toxic, mutagenic and among the most damaging chemical compounds with regard to living organisms. Because of their persistence and wide distribution removal from the environment is an important challenge. Here we report a new Nano container matrix based on the deep sea archaea-derived RHCC-Nanotube (RHCC-NT), which rapidly and preferentially binds low molecular weight PAHs. Under controlled-laboratory conditions and using fluorescence spectroscopy in combination with X-ray crystallography and MD simulations, we quantified the real-time binding of low molecular weight PAHs (2–4 rings) to our substrate. Binding coefficients ranged from 5.4 ± 1.6 (fluorene) to 32 ± 7.0 μM (acenaphthylene) and a binding capacity of 85 pmoles PAH per mg RHCC-NT, or 2.12 μmoles in a standard 25 mg sampler. The uptake rate of pyrene was calculated to be 1.59 nmol/hr∙mol RHCC-NT (at 10 C). Our results clearly show that RHCC-NT is uniquely suited as a monitoring matrix for low molecular weight PAHs.

Graphical abstract The identification of discrete subsets of residues which respond to a local injection of thermal energy into the catalytic intermediates or cofactors within the active sites of GSAM, using non-equilibrium MD simulations of thermal diffusion, shows that the architecture of GSAM potentially supports a number of specific pathways for the flow of vibrational energy within and between the two subunits of the enzyme. Assuming that the thermal excitation with a heat bath acts as a physical proxy for chemical activity, these pathways may form the basis of a communication network for coordinating and triggering allosteric conformational changes in the two subunits by shuttling information about chemical modifications of the catalytic intermediates within the two active sites back and forth between the two subunits., Non-equilibrium molecular dynamics simulations of vibrational energy flow induced by the imposition of a thermal gradient have been performed on the μ2-dimeric enzyme glutamate-1-semialdehyde aminomutase (GSAM), the key enzyme in the biosynthesis of chlorophyll, in order to identify energy transport pathways and to elucidate their role as potential allosteric communication networks for coordinating functional dynamics, specifically the negative cooperativity observed in the motion of the two active site gating loops. Fully atomistic MD simulations of thermal diffusion were executed with a GROMACS simulation package on a fully solvated GSAM enzyme by heating various active site target ligands (initially, catalytic intermediates and cofactors) to 300K while holding the remainder of the protein and the solvent bath at 10K and monitoring the temperature T(t) of all the enzyme residues as a function of time over a 1ns observation window. Energy is observed to be deposited in a relatively small number of discrete chains of residues most of which contribute to specific structural or biochemical functionality. Thermal linkages between all thermally active chains were established by isolating a specific pair of chains and performing a thermal diffusion simulation on the pair, one held at 300K and the other at 10K, with the rest of the protein frozen in its initial atomic configuration and thus thermally unresponsive. Proceeding in this way, it was possible to map out multiple pathways of vibrational energy flow leading from one of the active sites through a network of contiguous residues, many of which were evolutionarily conserved and linked by hydrogen bonds, into the other active site and ultimately to the other gating loop.

Elemental sulfur exists primarily as an S80 ring and serves as terminal electron acceptor for a variety of sulfur-fermenting bacteria. Hyperthermophilic archaea from black smoker vents are an exciting research tool to advance our knowledge of sulfur respiration under extreme conditions. Here, we use a hybrid method approach to demonstrate that the proteinaceous cavities of the S-layer nanotube of the hyperthermophilic archaeon Staphylothermus marinus act as a storage reservoir for cyclo-octasulfur S8. Fully atomistic molecular dynamics (MD) simulations were performed and the method of multiconfigurational thermodynamic integration was employed to compute the absolute free energy for transferring a ring of elemental sulfur S8 from an aqueous bath into the largest hydrophobic cavity of a fragment of archaeal tetrabrachion. Comparisons with earlier MD studies of the free energy of hydration as a function of water occupancy in the same cavity of archaeal tetrabrachion show that the sulfur ring is energetically favored over water.