Disordered binding of small molecules to Aβ(12-28)

Area of Science:

• Biochemistry
• Computational Biology
• Neuroscience

Background:

• Alzheimer's disease is linked to amyloid-beta peptide (Aβ) aggregation.
• Small molecules and peptides are being investigated as inhibitors of Aβ aggregation.
• Aromatic moieties in inhibitors suggest a key role in Aβ interactions.

Purpose of the Study:

• To investigate the interaction mechanisms between aromatic small molecule inhibitors and monomeric Aβ(12-28).
• To determine if these inhibitors share a common mechanism of action.
• To elucidate the role of molecular dynamics in understanding inhibitor binding.

Main Methods:

• Atomistic molecular dynamics simulations at equilibrium.
• Analysis of Aβ(12-28) conformational ensemble at 300 K and neutral pH.
• Free energy landscape analysis to identify binding effects.

Main Results:

• Monomeric Aβ(12-28) exists as a partially collapsed ensemble lacking canonical secondary structure.
• Inhibitors exhibit varying affinities for Aβ(12-28), influenced by their aromatic and charged groups.
• No single binding mode dominates; inhibitors preferentially bind to the N-terminal region (residues 13-20).
• Inhibitors alter the free energy landscape, changing the population of loop-like conformers.

Conclusions:

• Intrinsic disorder of Aβ persists even when bound to small molecules.
• Inhibitors can modify monomeric Aβ properties through diverse and specific interactions.
• Understanding these interactions is crucial for developing effective Alzheimer's therapeutics.