Molecular Mechanisms of Selected Disease-Linked Proteins Studied Through Atomistic Molecular Dynamics Simulations
|Tila||Julkaistu - 8 marraskuuta 2019|
|Nimi||Tampere University Dissertations|
Due to the small scale of membrane proteins and their primary interaction part-
ners, lipids and ions, observing the molecular mechanisms and dynamics of protein function can be impossible by traditional experimental measurements. Here, we are able to bypass the visual limit by employing atomistic molecular dynamics simulations in order to study the properties of these membrane proteins. Understanding the dynamics of proteins at the atomistic level can be beneﬁcial for pharmaceutical development as drugs targeting membrane proteins are cures for many diseases. Our goal in this Thesis is to explore two different types of membrane proteins, to study the dynamics and molecular mechanisms of their native states at an atomistic level, and to employ various computational methods to establish potential links between their function and related diseases. The ﬁrst part of this Thesis focuses on P2, a major protein of the myelin sheath of the peripheral nervous system, active in stacking myelin leaﬂets together. Certain mutations in the gene encoding P2 have been connected with an inherited demyelinating disease, while other mutations have been found to affect P2 activity in other ways. We performed sets of simulations on the P2 wild type and a number of its point mutated variants in order to gain insight on its structural dynamics at an atomistic level, and found the point mutants to alter its properties. The results also provide clues on how the changed activity is related to the demyelinating diseases. We also discovered a mechanism for the opening of the P2 barrel structure, suggesting a similar mechanism for other fatty acid binding proteins as well. The research
was conducted alongside an experimental group allowing us to produce a wide and thorough study on the protein function. The second part of this Thesis focuses on rhodopsin, a G protein-coupled receptor (GPCR) of the visual transduction cycle. Recent studies have found rhodopsin to be a possible scramblase – to rapidly facilitate lipid translocation between the two
membrane leaﬂets, which is an essential element of cellular physiology. Scramblases are found in nearly every cellular membrane, yet the mechanisms behind their func tion have remained unknown at a molecular level. Their dysfunction has also been linked to a number of severe diseases. We extensively studied the molecular mechanisms with which rhodopsin is able to create an energetically favorable environmentfor scramblase-assisted lipid ﬂip–ﬂop and found its properties to be non-selective regarding the lipid headgroup. The mechanism functioned in a manner that could be generalized to other GPCRs as well.