The reconciliation between the experimental and calculated octanol-water partition coefficient of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine using atomistic molecular dynamics: an open question.

The octanol-water partition coefficient of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) was investigated using atomistic molecular dynamics simulations via thermodynamic integration and multistate Bennett acceptance ratio methods. The GAFF and CHARMM36 force fields were used with six water models widely used in molecular dynamics simulations. The OPC4 water model provided the best agreement with the experimental octanol-water partition coefficient of DPPC using the two force fields. However, there is still plenty of room for improvement in water models with correct estimation of surface tension that uses better and suitable non-bonded interaction parameters between water-water and water-DPPC. The Gibbs free energy of transferring DPPC from octanol to water phase was calculated to be 19.8 ± 0.3 and 20.2 ± 0.3 kcal mol-1, giving a partition coefficient of 14.5 ± 0.4 and 14.8 ± 0.3 for the GAFF and CHARMM36 force fields, respectively. This study reinforces the importance of developing new water models that reproduce experimental surface tensions to reconcile the water-water and water-DPPC non-bonded interactions and the existing discrepancy between experimental measurements of amphiphilic molecules that are important in many areas of scientific applications and industry such as biophysics, surfactant, colloids, membranes, medicine, nanotechnology, and food and pharmaceutical industries, and so on. It raises two important open questions: Is the experimental octanol-water partition coefficient of DPPC reliable? Or is its calculation accurate using the OPC4 water model? With respect to the experimental measurements, there may be non-treated aspects such as the formation of aggregates in aqueous phase and limit of detection of the applied method. And, in the calculation, some effects are not possible to be considered in a correct way or viable time such as calculating quantum effects, sampling all conformations, considering phase transitions, and correctly evaluating the intermolecular forces to estimate an accurate surface tension.Communicated by Ramaswamy H. Sarma.

Absolute binding free energies of the antiviral peptide ATN-161 with protein targets of SARS-CoV-2.

The interactions of the antiviral pentapeptide ATN-161 with the closed and open conformations of the α5ß1 integrin, the SARS-CoV-2 major protease, and the omicron variant spike protein complexed with hACE2 were studied using molecular docking and molecular dynamics simulation. Molecular docking was performed to obtain ATN-161 binding poses with these studied protein targets. Subsequently, molecular dynamics simulations were performed to verify the ligand stability at the binding site of each protein target. Pulling simulations, umbrella sampling, and weighted histogram analysis method were used to obtain the potential of mean force of each system and calculate the Gibbs free energy of binding for the ATN-161 peptide in each binding site of these protein targets. The results showed that ATN-161 binds to α5ß1 integrin in its active and inactive form, binds weakly to the omicron variant spike protein complexed with hACE2, and strongly binds to the main protease target.Communicated by Ramaswamy H. Sarma.

Absolute binding free energies of mucroporin and its analog mucroporin-M1 with the heptad repeat 1 domain and RNA-dependent RNA polymerase of SARS-CoV-2.

The peptide Mucroporin and its analog Mucroporin-M1 were studied using the molecular docking and molecular dynamics simulation of their complexation with two protein targets, the Heptad Repeat 1 (HR1) domain and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. The molecular docking of the peptide-protein complexes was performed using the glowworm swarm optimization algorithm. The lowest energy poses were submitted to molecular dynamics simulation. Then, the binding free energies of Mucroporin and its analog Mucroporin-M1 with these two protein targets were calculated using the Multistate Bennett Acceptance Ratio (MBAR) method. It was verified that the peptides/HR1 domain complex showed stability in the interaction site determined by molecular docking. It was also found that Mucroporin-M1 has a much higher affinity than Mucroporin to the HR1 protein target. The peptides showed similar stability and affinity at the NTP binding site in the RdRp protein. Additional experimental studies are needed to confirm the antiviral activity of Mucroporin-M1 and a possible mechanism of action against SARS-CoV-2. However, here we indicate that Mucroporin-M1 may have potential antiviral activity against the HR1 domain with the possibility for further peptide optimization.Communicated by Ramaswamy H. Sarma.

Lung surfactant negatively affects the photodynamic inactivation of bacteria-in vitro and molecular dynamic simulation analyses.

In the context of the rapid increase of antibiotic-resistant infections, in particular of pneumonia, antimicrobial photodynamic therapy (aPDT), the microbiological application of photodynamic therapy (PDT), comes in as a promising treatment alternative since the induced damage and resultant death are not dependent on a specific biomolecule or cellular pathway. The applicability of aPDT using the photosensitizer indocyanine green with infrared light has been successfully demonstrated for different bacterial agents in vitro, and the combination of pulmonary delivery using nebulization and external light activation has been shown to be feasible. However, there has been little progress in obtaining sufficient in vivo efficacy results. This study reports the lung surfactant as a significant suppressor of aPDT in the lungs. In vitro, the clinical surfactant Survanta® reduced the aPDT effect of indocyanine green, Photodithazine®, bacteriochlorin-trizma, and protoporphyrin IX against Streptococcus pneumoniae. The absorbance and fluorescence spectra, as well as the photobleaching profile, suggested that the decrease in efficacy is not a result of singlet oxygen quenching, while a molecular dynamics simulation showed an affinity for the polar head groups of the surfactant phospholipids that likely impacts uptake of the photosensitizers by the bacteria. Methylene blue is the exception, likely because its high water solubility confers a higher mobility when interacting with the surfactant layer. We propose that the interaction between lung surfactant and photosensitizer must be taken into account when developing pulmonary aPDT protocols.