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Structural and Pathway Complexity of β-Strand Reorganization within Aggregates of Human Transthyretin(105−115) Peptide
journal contribution
posted on 2007-05-17, 00:00 authored by Da-Wei Li, Li Han, Shuanghong HuoInterstrand conformational rearrangements of human transthyretin peptide (TTR(105−115)) within dimeric
aggregates were simulated by means of molecular dynamics (MD) with implicit solvation model for a total
length of 48 μs. The conformations sampled in the MD simulations were clustered to identify free energy
minima without any projections of free energy surface. A connected graph was constructed with nodes
(=clusters) and edges corresponding to free energy minima and transitions between nodes, respectively. This
connected graph which reflects the complexity of the free energy surface was used to extract the transition
disconnectivity graph, which reflects the overall free energy barriers between pairs of free energy minima
but does not contain information on transition paths. The routes of transitions between important free energy
minima were obtained by further processing the original graph and the MD data. We have found that both
parallel and antiparallel aggregates are populated. The parallel aggregates with different alignment patterns
are separated by nonnegligible free energy barriers. Multiroutes exist in the interstrand conformational
reorganization. Most visited routes do not dominant the kinetics, while less visited routes contribute a little
each but they are numerous and their total contributions are actually dominant. There are various kinds of
reptation motions, including those through a β-bulge, side-chain aided reptation, and flipping or rotation of
a hairpin formed by one strand.