The Design and Structure Prediction of Protein Oligomers

Detta är en avhandling från Department of Biochemistry and Structural Biology, Lund University

Sammanfattning: Popular Abstract in English Proteins are a class of biological macromolecules that perform countless fundamental and diverse functions in living organisms. Chemically speaking, they are polymers built out of monomeric units called amino acids. All biological proteins are constructed out of 20 different amino-acid types. To form protein molecules, amino acids are linked together in a linear chain like pearls on a string. The physical and chemical characteristics of proteins are determined by the sequence of amino acids. Some proteins play structural roles, serving as building blocks for many cellular architectures, while others act as regulators, signal receptors, or enzymes that catalyze various chemical transformations necessary for life. To carry out its biological function, a protein must “fold” into a specific three-dimensional structure. This structure is determined solely by the protein’s amino-acid sequence, which means that it could in theory be readily predicted. Such an endeavor would be extremely beneficial for many biological, medical, as well as industrial applications. This is because the information about protein structure is essential in research areas that aim to develop various protein-targeting drugs, as well as in research areas that aim to elucidate protein interaction networks (an important piece of information when treating various diseases for example). As experimental determination of protein structures is extremely laborious, time consuming, and costly, structure prediction offers an attractive alternative for such research endeavors. Furthermore, accurate structure prediction methods are a prerequisite for efficient protein design, the ultimate goal of which is to create new protein structures with predefined functions. As such, the field of protein design holds incredible potential for revolutionizing medicine, biology, as well as nanotechnology. However, problems faced by both protein structure prediction and protein design remain largely unsolved. In this work, we tackled some of the issues that plague these fields of research, with a specific focus on protein oligomers, which are structures assembled from multiple protein molecules that come together and interact closely. Protein oligomers are mostly homomeric, meaning that they are composed of multiple copies of the same protein, and almost exclusively possess some form of symmetry. Here we focused on two classes of protein oligomers: coiled coils and icosahedral viral capsids. Coiled coils are an important class of protein oligomers that perform a number of essential biological functions, including the regulation of gene expression, cell division, viral infection etc. In paper I, we developed a method that can predict the structures and oligomeric states of homomeric coiled coils with approximately 70% accuracy. In addition to being able to provide structural models of coiled coils, this method can further aid the experimental determination of coiled-coil structures. Without accurate structural models of proteins whose structure we wish to determine experimentally, the structure solving process can be extremely laborious and time consuming. The availability of accurate structural models makes this endeavor much simpler. This is what we did in paper II: used the predicted structures of coiled coils to actually obtain the true, experimentally determined structures. In paper III, we further designed a coiled-coil oligomerization switch that forms one type of assembly in solutions of low acidity, and a completely different type of assembly in solutions of high acidity. Such a system could be beneficial in synthetic biology as a biosensor for example. In paper IV, we focused on developing a container capable of encapsulating specific protein cargo. Such systems are of great benefit in medicine for instance, as they can be used to deliver encapsulated drugs and/or imaging probes to specific organs, tissues, and cells.