Computational Methods and Models for Atomistic Simulations of Ion Hydration, Ion-Ligand Complexes, and Ion Transport in Channels

Ions are omnipresent in Nature and play significant roles in a large number of biological and nanotechnological applications. For example, the investigation of their coordination with ligands is a recurrent theme in the scientific literature, with special reference to catalytic activity, nucleic acid cleavage, and anticancer drug studies. Besides, in the context of biological channels, ions may generate various kinds of ionic currents crucial for human physiological activities, like movement and heartbeats. Over the past seventy years, numerous experimental and theoretical techniques have been developed to address several properties of ions in aqueous solutions and in interaction with proteins, such as ion coordination, hydration free energy, ligand exchange times, and ionic currents in biochannels. In this regard, molecular dynamics (MD) simulations have proved very fruitful in providing a deep atomistic understanding of both complex and subtle phenomena involving ions. In this dissertation, novel computational approaches and applications are presented aiming at a better comprehension of different aspects of ion microsolvation, ion-ligand complex formation, and ion transport into protein channels, thus extending the range of available in silico techniques in this research area. The dissertation is structured into three parts. The first part of this thesis introduces a new computational methodology for analyzing the structural, thermodynamic, and kinetic properties of ion microsolvation, particularly effective in studying aqua-ion complex formation and solvent exchange in the first hydration shell, beyond the reach of standard MD simulations. The second part enhances the accuracy of force fields for ion-carboxylate interactions and subsequently presents a computational procedure for assessing stability constants and ligand exchange rates. This procedure, adaptable to different ions and ligands, shows promise in elucidating ion-ligand exchange mechanisms and predicting dissociation rates up to seconds, thus expanding applications of the method to more complex systems. The third part firstly discusses software developed for analyzing pore morphology and ion translocation pathways, and secondly the use of MD simulations and master-equations for the Kv4.3 potassium channel. In the latter, both techniques combined proved to be useful tools coupled with experiments to disclose the molecular causes of detrimental point mutations of the Kv4.3 potassium channel. Although the application areas of the above studies may appear diverse, each research work contributes consistently to a deeper understanding of the underlying molecular mechanisms characterizing ion solutions and strives to align computational models with experimental conditions, thus pushing the boundaries of the in silico research in this domain.