A New Mixed All-Atom/Coarse-Grained Model: Application to Melittin Aggregation in Aqueous Solution.

Area of Science:

• Computational chemistry
• Biophysics
• Molecular modeling

Background:

• All-atom models are computationally expensive for studying peptide aggregation.
• Peptide aggregation is crucial for understanding biologic formulation and function.
• Melittin is a model peptide known for its aggregation propensity.

Purpose of the Study:

• Introduce and validate a novel mixed-resolution simulation method (AACG) for peptide aggregation.
• Characterize the aggregation process of melittin using the AACG approach.
• Assess the impact of environmental factors on melittin aggregation.

Main Methods:

• Developed an all-atom/coarse-grained (AACG) simulation technique.
• Represented peptide atoms fully and water molecules as single sites.
• Incorporated long-range electrostatic interactions using Ewald summation.

Main Results:

• Achieved 3-4x speedup in CPU time and ~7x in diffusion compared to all-atom models.
• Observed melittin aggregate formation, characterizing size distribution and buried surface areas.
• Identified key interactions (e.g., π-cation, π-stacking) and demonstrated salt/temperature effects.

Conclusions:

• The AACG method is efficient for studying peptide aggregation and relevant for biologics.
• Simulations support the molten globule model for melittin aggregates.
• AACG can guide the formulation and design of therapeutic peptides.