Cedrix Jurgal Dongmo Foumthuim

Unconventional amphiphilic molecules having a rigid hydrophobic central unit and flexible or semiflexible hydrophilic chains on the rim have proven valuable in several technological applications, for example, host-guest chemistry. The further presence of alternating hydrophobic and hydrophilic tails complicates the definition of clear core and shell regions, resulting in complex segregation and frustrated self-assembly. In this study, we investigate symmetric triphenylene-based amphiphilic derivatives with alternating benzyl and alkylsulfonate groups. We characterize their self-assembly in water and different solutions using several experimental techniques, including NMR, atomic force microscopy, dynamic light scattering, and small-angle X-ray and neutron scattering, alongside extensive molecular dynamics simulations, including both atomistic and coarse-grained integrative modeling with metainference. In aqueous solutions, these amphiphiles form stacked assemblies, adopting alternate up-down conformations driven by π-stacking of up to six molecules. The introduction of NaCl salt screens unfavorable electrostatic interactions, thus promoting further π-stacking and leading to the formation of larger elongated aggregates.

Unconventional amphiphilic molecules having a rigid hydrophobic central unit and flexible or semiflexible hydrophilic chains on the rim, have proven valuable in several technological applications, for example host-guest chemistry. The further presence of alternating hydrophobic and hydrophilic tails complicates the definition of clear core and shell regions, resulting in complex segregation and frustrated self-assembly. In this study, we investigate symmetric triphenylene-based amphiphilic derivatives with alternating benzyl and alkylsulfonate groups. We characterize their self-assembly in water and different solutions using several experimental techniques – NMR, atomic force microscopy, dynamic light scattering, small-angle X-ray and neutron scattering – alongside extensive molecular dynamics simulations, both atomistic and coarse-grained integrative modelling with metainference. In aqueous solutions, these amphiphiles form stacked assemblies, adopting alternate up-down conformations driven by π-stacking of up to six molecules. The introduction of NaCl salt screens unfavorable electrostatic interactions thus promoting further π-stacking and leads to the formation of larger elongated aggregates.

Unconventional amphiphilic molecules having a rigid hydrophobic central unit and flexible or semiflexible hydrophilic chains on the rim, have proven valuable in several technological applications, for example host-guest chemistry. The further presence of alternating hydrophobic and hydrophilic tails complicates the definition of clear core and shell regions, resulting in complex segregation and frustrated self-assembly. In this study, we investigate symmetric triphenylene-based amphiphilic derivatives with alternating benzyl and alkylsulfonate groups. We characterize their self-assembly in water and different solutions using several experimental techniques – NMR, atomic force microscopy, dynamic light scattering, small-angle X-ray and neutron scattering – alongside extensive molecular dynamics simulations, both atomistic and coarse-grained integrative modelling with metainference. In aqueous solutions, these amphiphiles form stacked assemblies, adopting alternate up-down conformations driven by π-stacking of up to six molecules. The introduction of NaCl salt screens unfavorable electrostatic interactions thus promoting further π-stacking and leads to the formation of larger elongated aggregates.

The effect of cosolvents urea and trimethylamine-N-oxide (TMAO) on hydrophobic association mechanisms is investigated by employing molecular dynamics simulations and free energy calculations. Three nonpolar moieties are used to model the hydrophobic interactions: n-hexane nC₆H₁₄, neopentane C₅H₁₂, and cyclohexane cC₆H₁₂. These hydrophobic model systems are subsequently immersed in four different solvent models with varied composition: pure water, aqueous urea, aqueous TMAO, and mixed urea-TMAO ternary solution. The solute-solute potentials of mean force (PMF), solute-water, and solute-cosolvent distribution functions are reported. Both urea and TMAO are found to have only moderate effects on hydrophobic associations, thereby mainly acting as glue bridging between pairwise hydrophobic moieties holding them together. Furthermore, it is seen that TMAO mediates the formation of hydrogen bonds between its oxygen atom and water or urea while still favoring the hydrophobic contacts with the hydrophobic surface, thereby acting as a kind of amphiphile displacing water or urea from the inner solvation shell of the hydrophobic solutes investigated here to the bulk. The analyses of the enthalpic and entropic contributions to PMFs indicate that configurations at the contact minimum are both enthalpically and entropically favorable, though, with a large entropic contribution, whereas solute-separated minimum configurations are dominantly enthalpically driven, induced by stabilizing water hydrogen bonding. To provide a more factual and general perspective to the simplistic hydrophobic models, simulations are also performed on a realistic-like hydrophobic model, β2-microglobulin (β2m), a paradigmatic protein model for amyloid studies. Results show that TMAO protects the β2m folded state by its strong preferential exclusion from the close vicinity of its surface. Contrariwise, urea moieties likely accumulate at the protein surface, thereby displacing water molecules from the hydration shell to the bulk, thus promoting an unfolded state of the protein.

Infrared C=O stretching bands of thymine are computed using a hybrid quantum-classical approach, revealing how stacking and hydrogen bonding interactions in single-stranded DNA influence the spectral lineshape.

Solvation properties of poly-phenylacetylene synthetic foldamer (pPA) (left) and phenylalanile oligopeptide (PHE) (right), in three solvents. PHE is entropy–enthalpy compensating in water, pPA is displaying a large dominance of the enthalpic part.

An aqueous environment is vital for life as we know it, and water is essential for nearly all biochemical processes at the molecular level. Proteins utilize water molecules in various ways. Consequently, proteins must transport water molecules across their internal network of tunnels to reach the desired action sites, either within them or by functioning as molecular pipes to control cellular osmotic pressure. Despite water playing a crucial role in enzymatic activity and stability, its transport has been largely overlooked, with studies primarily focusing on water transport across membrane proteins. The transport of molecules through a protein's tunnel network is challenging to study experimentally, making molecular dynamics simulations the most popular approach for investigating such events. In this study, we focused on the transport of water molecules across three different α/β-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase. Using a 5 μs adaptive simulation per system, we observed that only a few tunnels were responsible for the majority of water transport in dehalogenase, in contrast to a higher diversity of tunnels in other enzymes. Interestingly, water molecules could traverse narrow tunnels with subangstrom bottlenecks, which is surprising given the commonly accepted water molecule radius of 1.4 Å. Our analysis of the transport events in such narrow tunnels revealed a markedly increased number of hydrogen bonds formed between the water molecules and protein, likely compensating for the steric penalty of the process. Overall, these commonly disregarded narrow tunnels accounted for ∼20% of the total water transport observed, emphasizing the need to surpass the standard geometrical limits on the functional tunnels to properly account for the relevant transport processes. Finally, we demonstrated how the obtained insights could be applied to explain the differences in a mutant of the human soluble epoxide hydrolase associated with a higher incidence of ischemic stroke.

An aqueous environment is vital for life as we know it, and water is essential for nearly all biochemical processes at a molecular level. Proteins utilize water molecules in various ways. Consequently, proteins must transport water molecules across their internal network of tunnels to reach the desired action sites, either within them or functioning as molecular pipes to control cellular osmotic pressure. Despite water playing a crucial role in enzymatic activity and stability, its transport has been largely overlooked, with studies primarily focusing on water transport across membrane proteins. The transport of molecules through a protein’s tunnel network is challenging to study experimentally, making molecular dynamics simulations the most popular approach for investigating such events. In this study, we focused on the transport of water molecules across three different α/β-hydrolases: haloalkane dehalogenase, epoxide hydrolase, and lipase. Using a 5 μs adaptive simulation per system, we observed that only a few tunnels were responsible for the majority of water transport in dehalogenase, in contrast to a higher diversity of tunnels in other enzymes. Interestingly, water molecules could traverse narrow tunnels with sub-angstrom bottlenecks, which is surprising given the commonly accepted water molecule radius of 1.4 Å. Our analysis of the transport events in such narrow tunnels revealed a markedly increased number of hydrogen bonds formed between the water molecules and the protein, likely compensating for the steric penalty of the process. Overall, these commonly disregarded narrow tunnels accounted for ∼20% of the total water transport observed, emphasizing the need to surpass the standard geometrical limits on the functional tunnels to properly account for relevant transport processes. Finally, we demonstrated how the obtained insights could be applied to explain the differences in a mutant of the human soluble epoxide hydrolase associated with a higher incidence of ischemic stroke.

Synthetic polymers assume a compact/extended conformation in a poor/good solvent. Proteins, formed by both hydrophobic and polar moieties fold in water but not in apolar solvents. This difference can be rationalized and quantified by calculating the solvation free energy.