Metal ions in life : towards accurate computer-aided studies ofprotein-ion interactions

Sammanfattning: The importance of ions in life sciences can not be overstated. The interaction betweenmetal ions and proteins is vital because it is involved in a variety of biological processes.The ions contribute to stability and function of proteins. Moreover, they are relevant indisease progression.Realistic computer simulations pave the way for drug development, through providingdetailed insights into the dynamics of proteins and various biological processes thatoccur in the body. Such information can be impossible to achieve through experimentsof living subjects in vivo or from test tube experiments in vitro alone. However,theoretical methods have to result in accurate predictions. In my thesis, I studieddifferent ways to handle the ions in simulations. Since the systems contain thousands ofatoms the calculations are demanding. Despite the availability of computer clusters, thecom putational capacity is not sufficient. I have examined the simplified models used insimulations of larger systems (e.g., whole proteins) to pave the way for improvements ofthe simulation models.Different ions have different effects on biochemical systems and it is important to beable to distinguish between them. Thus, from a biochemical point of view, it is centralto be able to describe their unique characteristics. Their difference can be from vital totoxic to the body. Zinc is essential and present in more than 3000 proteins in our bodyand has a very flexible interaction with proteins. This property has proved to be hard toreproduce in computer simulations. Cadmium can replace zinc, but is toxic because itdoes not have the same catalytic ability. From a modelling perspective do these ions havesimilar characteristics as they have the same ionic charge. Inclusion of more realisticelectron effects may be necessary to be able to simulate the difference.With my studies, I have contributed towards a better understanding of the interactionsbetween metal ions and proteins. I have pointed out a direction for further improvementof methods for simulations of large systems.For the same purpose, I have also studied the frequently occurring ions sodium andpotassium found as salts in all body fluids, but also lithium belonging to the same groupin the periodic table and used in therapeutic purposes. The results show that potassiumand sodium can be simulated by a commonly used computational approach, whereasmore advanced methods are required to study lithium ions accurately.Overall, the work within this thesis has explored ion-protein interactions and providedinformation about methods for energy calculations and models for molecular dynamicssimulations for some of the most important ions within biochemistry.