Forcefield_NCAA

Forcefield_NCAA provides self-consistent AMBER force field parameters compatible with the AMBER ff03 force field for a library of 147 non-canonical amino acids (including β- and N-methylated variants) to support molecular simulations and peptide/protein design.

Key Features:

• Force field library: A comprehensive set of self-consistent AMBER parameters for 147 non-canonical amino acids compatible with AMBER ff03.
• Charge derivation: Ab initio-derived partial charges optimized using the Restrained Electrostatic Potential (RESP) fitting approach.
• Topology and parameter outputs: Generation of AMBER-ready topology and parameter files for incorporation into simulations.
• Validation against experiment: Parameter validation using discrimination of active and inactive Compstatin analogs with experimental IC50 data.
• Molecular simulation support: Use of short molecular dynamics simulations to evaluate analog behavior.
• Binding affinity calculations: Support for approximate binding affinity (K*) estimation and binding free energy calculations using Molecular Mechanics-Generalized Born Surface Area (MM-GBSA), with MM-GBSA shown to perform better in distinguishing actives.
• Interaction parameter control: Parameters that capture and allow adjustment of size, van der Waals interactions, and electrostatics for NCAAs.
• Comparative interaction analysis: Enables examination of critical interactions in potent Compstatin analogs containing NCAAs versus analogs with only natural amino acids or native Compstatin.

Scientific Applications:

• Peptide and protein design: Enabling inclusion of 147 non-canonical amino acids (including β- and N-methylated variants) in de novo protein and peptide design workflows.
• Structure prediction and modeling: Supporting molecular dynamics and energy-based evaluations for protein structure prediction involving NCAAs.
• Binding affinity and lead optimization: Facilitating binding free energy estimation (MM-GBSA) and K* calculations to discriminate active versus inactive Compstatin analogs using experimental IC50 for validation.
• Peptide therapeutic development: Providing parameters for exploring amino acid modifications in peptide-based therapeutic design and molecular engineering.

Methodology:

Ab initio-derived partial charges fitted with RESP; short molecular dynamics simulations; binding free energy calculations including MM-GBSA and approximate K* estimation; generation of AMBER-ready topology and parameter files.