Efficient construction of a diverse conformational library for amyloid-β as an intrinsically disordered protein

Structural characterization of intrinsically disordered proteins (IDPs) is paramount and challenging in structural biology. In this regard, a de novo computational protocol is introduced to build heterogeneous structural libraries for amyloid-β (Aβ) as a critical IDP. This method combines the strength of the simulated annealing - in jumping over energy barriers and escaping from traps - with short conventional molecular dynamics simulations to quickly explore local regions of the conformational space. The protocol efficiency and reliability in building Aβ conformational library is compared with two widely used simulation methods, replica exchange molecular dynamics and multiple trajectory sampling. The probability distribution functions of various structural and energetic features are constructed for each library, and also the diversity and convergence rates in these protocols were compared. Our results show that the suggested protocol is a successful computational method in the generation of a diverse conformational library of the Aβ monomer in agreement with experimental data. This method focuses on visiting more conformations in less computational time without paying attention to the statistical weight of each state in the library. We believe that the suggested computational technique can be used for generating a reasonable starting pool for subsequent reweighting with experimental data to obtain a statistical ensemble.