Department of physics, Fudan University, Shanghai, China

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Department of physics, Fudan University, Shanghai, 200433 China Thermodynamics and dynamics of amyloid peptide oligomerisation are sequence-dependent Yan Lu, Guanghong Wei Department of physics, Fudan University, Shanghai, 200433 China Abstract: More than 20 human diseases are associated with the pathological self-assembly of soluble proteins into cytotoxic oligomers and amyloid fibrils. Two peptides from 2-microglobulin and amyloid- peptide are selected to study the thermodynamics and dynamics of amyloid peptide oligomerisation by MD simulations. Based on multiple trajectories runs, we find that the two peptides share common, but also very different aggregation properties. Notably, an increase in the hydrophobic character of the peptide, as observed in Aβ16-22 with respect to 2m83-89, impacts the thermodynamics by reducing the population of amyloid-competent assemblies. Higher hydrophobicity is also found to slow down the dynamics of β-sheet formation by enhancing the averaged life time of all the aggregates and by reducing the complexity of the transition probability matrix between all configuration types. a) Clusters b) Free energy Landscape Model and method MD simulations with the OPEP coarse-grained force field a) Peptide model β2m (83-89) -------NHVTLSQ Aβ (16-22) ---------KLVFFAE b) Simulation time For each peptide system: 16 MD runs and 100-300 ns for each run Index CL Configuration Type Percentage sd 1 4.732 4+3+1 18.5% (19.1%) 1.1% 2 6.146 3+2+1+1+1 13.2% (14.5%) 0.9% 3 5.414 4+2+1+1 12.7% (12.1%) 0.7% 4 4.000 4+4 11.4% (8.7%) 2.1% 5 5.464 3+3+1+1 9.5% (10.7%) 6 6.000 4+1+1+1+1 8.2% (7.3%) 0.6% 7 6.732 3+1+1+1+1+1 7.8% (8.3%) 8 6.828 2+2+1+1+1+1 4.0% (4.6%) 0.4% 9 7.414 2+1+1+1+1+1+1 3.1% (3.5%) 0.5% 10 5.236 5+1+1+1 2.6% (2.0%) 0.3% Index CL Configuration Type Percentage sd 1 6.146 3+2+1+1+1 33.7% (31.1%) 4.1% 2 6.828 2+2+1+1+1+1 24.7% (23.7%) 2.7% 3 7.414 2+1+1+1+1+1+1 9.3% (6.3%) 1.5% 4 6.732 3+1+1+1+1+1 8.8% (7.2%) 1.3% 5 5.464 3+3+1+1 5.3% (8.5%) 1.7% 6 5.414 4+2+1+1 3.7% (5.5%) 1.1% 7 8.000 1+1+1+1+1+1+1+1 3.5% (1.4%) 2.2% 8 6.243 2+2+2+1+1 3.4% (4.8%) 9 5.560 3+2+2+1 3.3% (5.1%) 1.8% 10 6.000 4+1+1+1+1 1.8% (2.5%) 0.8% Probability of connectivity length (CL) of 2M(83-89) (upper) and A(16-22) (lower) aggregates sampled in all the MD runs. The CL percentage obtained in the second half of the MD runs is given in the parenthesis. The standard deviations (sd) of the CL percentage over 16 different runs is given also. Normalized probability of the different β-sheet sizes observed in all the 16 MD runs of β2m(83-89) and Aβ(16-22) 8-mers. Free energy surfaces (kcal/mol) of the two peptides-----β2m(83-89) (upper) and Aβ(16-22) (lower). c) Time evolution d) Transition matrix Transition probability matrices between the ten dominant configurations types of 2M(83-89) (left) and A(16-22) (right) Time evolution of the normalized probabilities of the configuration types (CT) and connectivity lengths (CL) sampled in two simulations of β2m(83-89) (upper) and Aβ(16-22) (lower) respectively. Summary: Our long molecular dynamics simulations show that an increase in the hydrophobic character of the peptide, as observed in Aβ16-22 with respect to β2m83-89, introduces an element of frustration that increases the proportion of visited amorphous structure and decreases the population of amyloid-competent assemblies, slowing down the dynamics of β-sheet formation by enhancing the averaged life time of the partially ordered aggregates.