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

Abstract

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

Keywords:

• Alchemical methods
• free energy calculations
• distribution coefficients
• amphiphilic molecules
• surfactants
• phospholipids
• hydrophobicity

Acknowledgments

The authors are also thankful to Dr. Shuxiang Li, Dra. Anna Panchenko, Dr. Alexey Shaytan, Dr. Matti Javanainen, Dr. Saad Izadi, who provided input files and helped us with some hints to run the simulations with the OPC water models.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors are thankful to CNPq (Grants 573560/2008-0, 465259/2014-6 and 302554/2017-3), CAPES (Finance Code 001), and FAPESP (Grant 2014/50983-3). The authors also acknowledge the FAPERJ NanoHealth Research Network (E-26/010.000983/2019). The FAPERJ Support Program for Thematic Projects in the State of Rio de Janeiro (210.104/2020) and the National Institute of Science and Technology Complex Fluids (INCT-FCx) for funding. ASP was recently awarded the Scientist of Our State by FAPERJ (201.186/2022). He also thanks the research productivity fellowship granted by CNPq (310166/2020-9).