Molecular Dynamics simulation of the hERG channel assisting Precision Medicine in Channelopathies

In the last two decades, a revolution in biology has shifted the traditional reductive approach to a bottom-up study of virtual models. This discipline, known as System Biology, integrates information coming from individual components, in order to predict the functioning of biological systems, with the idea that complex systems are made up of many independent components that can interact within well-structured networks changing over time, and that the functional properties of biological systems emerge as a consequence of interactions among their components. This paradigm shift is enabled by rapid advancements in technologies providing high-throughput instruments able to analyse in detail biological processes at the single molecule and single cell scale. The vast amount of data produced by these experimental techniques asks for adequate methods of analyses. The present dissertation focues on structural based methods for simulating the functioning of biological molecules, and in particular on the role of Molecular Dynamics simulations. The advantage of Molecular Dynamics simulations is that it is based on physical description of the systems, and consequently it might offer an atomistic description of the process under investigation. The first chapter of this thesis will provide an introduction on the role of Molecular Genetics and Biology in Medicine, also considering new challenges for the prediction of protein interactions and for development of Precision Medicine. In the Second Chapters, Molecular Dynamics simulations will be discussed, with an emphasis on the methods for data analysis adopted in the research projects presented in the second part of the thesis. The third Chapter will be present the main research project produced during my PhD: the study of inactivation and drug binding in the hERG potassium channel. Side project and parallel collaborations are briefly discussed in the fourth Chapter, followed by concluding remarks.