Passive permeation through biological membranes is an important mechanism for transporting molecules and regulating the cellular content. Studying and understanding passive permeation is also extremely relevant to many industrial applications, including drug design and nanotechnology. In vivo membranes typically consist of mixtures of lamellar and nonlamellar lipids. Lamellar lipids are characterised by their tendency to form lamellar bilayer phases, which are predominant in biology. Nonlamellar lipids, when isolated, instead form non-bilayer structures such as inverse hexagonal phases. While mixed lamellar/nonlamellar lipid membranes tend to adopt the ubiquitous bilayer structure, the presence of nonlamellar lipids is known to have profound effects on key membrane properties, such as internal distributions of stress and elastic properties. This dissertation examines permeation through lamellar and nonlamellar lipid membranes by utilising atomistic molecular dynamics simulations in conjunction with two di erent methods, the z-constraint and the z-restraint, in order to obtain transfer free energy profiles, diffusion profiles and permeation coefficients. An assessment of these methods is performed in search for the optimal, with the goal to create an automated, accurate and robust permeation study framework. Part of the dissertation involves the creation of the corresponding software. Furthermore, this work examines the effect of changing the lamellar vs. nonlamellar lipid composition on the passive permeation mechanism of a series of 13 small molecules and drugs. These nonlamellar lipids are known to affect the lateral pressure distribution inside the membranes. This work investigates the hypothesis that the differences in lateral pressure should increase the resistance to permeation. The results indicate that, upon addition of nonlamellar lipids, permeation is hindered for small molecules but is facilitated for the largest. All results are in agreement with previous experimental and computational studies. This work represents an advancement towards the development of more realistic in silico permeability assays, which may have a substantial future impact in the area of rational drug design.

Le mécanisme d‘interaction d‘un composé xénobiotique avec la membrane est un des facteurs clés qui influence son mécanisme d‘action biologique et donc son action thérapeutique pour un principe actif. Une analyse précise des interactions intermoléculaires à l‘échelle atomique peut être obtenue par dynamique moléculaire, une méthode qui apparait plus que jamais comme une alternative élégante aux techniques expérimentales. Les simulations de dynamique moléculaire permettent d‘évaluer ces interactions avec une résolution temporelle et spatiale difficiles à atteindre avec les méthodes expérimentales. Ces informations constituent une pierre angulaire de la compréhension des mécanismes d‘action des xénobiotiques . Les résultats obtenus corrèlent généralement bien avec les données expérimentales. Dans ce travail théorique, nous avons utilisé des dynamiques moléculaires non -biaisées et biaisées (z-Contraint). Nous avons étudié les modes d‘insertion (positionnement et orientation), les coefficients de partition, et la capacité de différents xénobiotiques à traverser la bicouche lipidique (perméation passive). Plusieurs composés de différentes familles thérapeutiques ont été étudiés (antiviraux, immunosuppresseurs et antioxydants), tous étant utilisés en transplantation d‘organes ; les antioxydants sont étudiés en tant que protecteurs d‘organe contre les phénomènes d‘ischémie -reperfusion. Pour la perméation passive, les profils d‘ énergies, les coefficients de diffusion locaux et la résistance à la traversée ont été calculés pour finalement obtenir des coefficients globaux de perméabilité. Nous avons montré que ces techniques de calcul donnent une description qualitative du processus d‘insertion/perméation, montrant notamment le rôle de différentes propriétés physiques (ex., polarité, charge). Des résultats remarquables ont été obtenus pour les larges molécules. Malgré la taille, ces mol cules peuvent s‘ insérer dans la bicouche lipidique relativement facilement (faibles barrières énergétiques). Par contre, leur diffusion dans les différentes régions de la membrane peut augmenter d‘une manière signifiante. Ce travail donne une confiance accrue dans les méthodes de dynamique moléculaire pour devenir prédictive dans les années avenirs, et aide de façon concrète les pharmacologues dans la recherche de nouvelles stratégies thérapeutiques. / The mechanism of interaction between drugs or any xenobiotic and membrane is one of thekey factors that affect its biological of action, and so its therapeutic activity. A thoroughrationalization of the relationship between the intrinsic properties of the xenobiotics and theirmechanism of interaction with membranes can now be assessed with atomistic details.Molecular dynamics (MD) is a powerful research tool to study xenobiotics-membraneinteractions, which can access time and space scales that are not simultaneously accessibleby experimental methods. Semi-quantitative molecular and thermodynamic descriptions ofthese interactions can be provided using in silico model of lipid bilayers, often in agreementwith experimental measurements.The main goal of our investigation consisted to get in depth insight into the mechanisms ofinteraction/partitioning/insertion/crossing with/in/into/through membrane and drug deliveryusing MD. In this thesis, we have focused on both drugs used in renal transplantation (e.g.,antivirals, immunosuppressants) and antioxidants, which can also be used to protect organsalong the transplantation processes. We have provided a series of clues showing that MDsimulations can tackle the delicate process of drug passive permeation.Both, unbiased and biased MD (z-constraint) simulations have been used to elucidate thexenobiotics-membrane interactions (i.e., positioning and orientation) and to evaluate crossingenergies, diffusion coefficients, and permeability coefficients. These findings led us to drawqualitative structure-permeability relationships (SPR). We have carefully analyzed how thechemical and physical properties of xenobiotics affect the mechanism of interactions andthus permeability. The robustness of these MD-based methodologies has been determinedto qualitatively predict these pharmacological parameters. Hydrophobic compounds showeda favorable partitioning into the lipid bilayer and relatively low Gibbs energy of crossing thecenter of membrane (ΔGcross). Hydrophilic or charged compounds showed partitioning closeto membrane surface, in interaction with the polar head groups and water molecules; this hasbeen shown to dramatically increase ΔGcross. Amphiphilic compounds are intermediatecompounds in terms of membrane insertion/positioning/crossing. It clearly appears that theyshould be analyzed case by case, an analysis for which MD simulations could be particularlysupportive. Also the influence of size at predicting permeation has been studied (i.e.,relatively large drugs were tested). The molecular size has shown no significant influence onΔGcross whereas diffusion coefficients were significantly affected, depending on themembrane regions.