Analysis of the protein-Ligand and protein-peptide interactions using a combined sequence- and structure-based approach

Proteins participate in most of the important processes in cells, and their ability to perform their function ultimately depends on their three-dimensional structure. They usually act in these processes through interactions with other molecules. Because of the importance of their role, proteins are also the common target for small molecule drugs that inhibit their activity, which may include targeting protein interactions. Understanding protein interactions and how they are affected by mutations is thus crucial for combating drug resistance and aiding drug design. This dissertation combines bioinformatics studies of protein interactions at both primary sequence and structural level. We analyse protein-protein interactions through linear motifs, as well as protein-small molecule interactions, and study how mutations affect them. This is done in the context of two systems. In the first study of drug resistance mutations in the protease of the human immunodeficiency virus type 1, we successfully apply molecular dynamics simulations to estimate the effects of known resistance-associated mutations on the free binding energy, also revealing molecular mechanisms of resistance. In the second study, we analyse consensus profiles of linear motifs that mediate the recognition by the mitogen-activated protein kinases of their target proteins. We thus gain insights into the cellular processes these proteins are involved in