Potential of mean force and molecular dynamics study on the transient interactions between a and beta synuclein that drive inhibition of alpha-synuclein aggregation

摘要

Self-association of alpha-synuclein (alpha S) into pathogenic oligomeric species and subsequent formation of highly ordered amyloid fibrils is linked to the Parkinson's disease. So most of the recent studies are now focused on the development of potential therapeutic strategies against this debilitating disease. beta-synuclein (beta S), a presynaptic protein that co-localizes with alpha S has been recently reported to act as an inhibitor of alpha S self-assembly. But the specificity of molecular interaction, nature and location between alpha S/beta S is not known despite the potential importance of beta S as an inhibitor of alpha S. We used molecular dynamics and potential of mean force (PMF) to study association of alpha S/beta S and alpha S/alpha S. The calculated PMF indicates that contact wells are significantly deeper and presence of a minimum at alpha S/beta S separation of 13.5 angstrom with a free energy barrier of 40 kcal/mol. We observed the dissociation energy barrier to be two times higher for the hetero-dimer (alpha S/beta S) than the homo-dimer (alpha S/alpha S). We also carried out umbrella samplings involving two degrees of freedom (one being the distance between the monomeric units and the other angle between the long axes of the two monomeric chains) and observed similar PMF profile. We noticed relatively stronger range of transient interactions between the monomeric units in hetero-dimer (alpha S/beta S) than homo-dimer (alpha S/alpha S). So our findings suggest that alpha S readily combines with beta S to form hetero-dimer than combining with itself in forming homo-dimer. Hence we see predominant transient interactions between alpha S and beta S can be used to drive inhibition of alpha S aggregation.