Molecular dynamics simulation is a very powerful tool to understand biomolecular processes. In this chapter, we go over different applications of this methodology to drug delivery systems (DDS) carried out in the group. DDS—a formulation or a device that enables the introduction of a therapeutic substance in the body and improves its efficacy and safety by controlling the rate, time, and place of release of drugs—are an important component of drug development and therapeutics. Biocompatible nanoparticles are materials in the nanoscale that emerged as important players, improving efficacy of approved drugs, for example. The molecular understanding of the encapsulation process could be very helpful to guide the nanocarrier for a specific system. Here we discuss different applications of drug delivery carriers, such as liposomes, polymeric micelles, and polymersomes using atomistic and coarse grain (CG) molecular dynamics simulations.

This paper presents a new model for polymersomes developed using a poly(ethylene oxide)-poly(butadiene) diblock copolymer bilayer. The model is based on a coarse-grained approach using the MARTINI force field. Since no MARTINI parameters exist for poly(butadiene), we have refined these parameters using quantum mechanical calculations and molecular dynamics simulations. The model has been validated using extensive molecular dynamics simulations in systems with several hundred polymer units and reaching up to 6 $\mu$ s. These simulations show that the copolymer coarse grain model self-assemble into bilayers and that NPT and NP_NγT ensemble runs reproduce key structural and mechanical experimental properties for different copolymer length chains with a similar hydrophilic weight fraction.

Connexinophaties are a collective of diseases related to connexin channels and hemichannels. In particular many Cx26 alterations are strongly associated to human deafness. Calcium plays an important role on this structures regulation. Here, using calcium as a probe, extensive atomistic Molecular Dynamics simulations were performed on the Cx26 hemichannel embedded in a lipid bilayer. Exploring different initial conditions and calcium concentration, simulation reached similar to 4 mu s. Several analysis were carried out in order to reveal the calcium distribution and localization, such as electron density profiles, density maps and distance time evolution, which is directly associated to the interaction energy. Specific amino acid interactions with calcium and their stability were capture within this context. Few of these sites such as, GLU42, GLU47, GLY45 and ASPS degrees, were already suggested in the literature. Besides, we identified novel calcium biding sites: ASP2, ASP117, ASP159, GLU114, GLU119, GLU120 and VAL226. To the best of our knowledge, this is the first time that these sites are reported within this context. Furthermore, since various pathologies involving the Cx26 hemichannel are associated with pathogenic variants in the corresponding CJB2 gene, using ClinVar, we were able to spatially associate the 3D positions of the identified calcium binding sites within the framework of this work with reported pathogenic variants in the CJB2 gene. This study presents a first step on finding associations between molecular features and pathological variants of the Cx26 hemichannel.