Effect of Disease Causing Missense Mutations on Intrinsically Disordered Regions in Proteins

Abstract

Background: It is well known that disease-causing missense mutations (DCMMs) reduce the structural stability/integrity of the proteins with well-defined 3D structures, thereby impacting their molecular functions. However, it is not known in what way DCMMs affect the intrinsically disordered proteins (IDPs) that do not adopt well defined stable 3D structures. Methods: In order to investigate how DCMMs may impact intrinsically disordered regions (IDRs) in proteins, we undertook Molecular Dynamics (MD) based studies on three different examples of functionally important IDRs with known DCMMs. Our studies revealed that the functional impact of DCMMs is in reducing the conformational heterogeneity of IDRs, which is intrinsic and quintessential for their multi-faceted cellular roles. Results: These results are reinforced by energy landscapes of the wildtype and mutant IDRs where the former is characterized by many local minima separated by low barriers, whereas the latter are characterized by one global minimum and several local minima separated by high energy barriers. Our MD based studies also indicate that DCMMs stabilize very few structural possibilities of IDRs either by the newly formed interactions induced by the substituted side chains or by means of restricted or increased flexibilities of the backbone conformations at the mutation sites. Conclusion: Furthermore, the structural possibilities stabilized by DCMMs do not support the native functional roles of the IDRs, thereby leading to disease conditions.