FoldDesign

FoldDesign generates de novo protein folds using sequence-independent fragment assembly simulations to explore protein structure and function space beyond templates in the Protein Data Bank (PDB).

Key Features:

• Structure-Independent Design: Uses specific secondary structure (SS) assignments to generate novel protein folds without relying on pre-existing sequences or templates.
• Replica-Exchange Monte Carlo Simulations: Performs sequence-independent replica-exchange Monte Carlo (REMC) simulations to assemble fragments and sample conformational space.
• High Structural Fidelity: On 354 non-redundant topologies, recapitulates an average of 87.7% of input SS elements and yields scaffolds with buried and solvent-exposed residue patterns resembling native proteins.
• Novel Global Folds: Produces scaffolds whose global folds are distinct from natural proteins in the PDB while maintaining local SS fidelity.
• Optimal Energy Force Field and Auxiliary Movements: Employs an energy force field with balanced SS packing terms and utilizes multiple auxiliary movements to enhance REMC sampling.
• Recognition of Uncommon Super-SS Geometries: Recognizes and assembles uncommon super-secondary structure (super-SS) geometries to enable generation of novel folds.

Scientific Applications:

• Exploration of Novel Fold Space: Enables discovery of protein scaffolds beyond evolutionary and PDB-derived structural space.
• Protein Function and Mechanism Studies: Facilitates investigation of structure–function relationships using designed scaffolds with tailored SS arrangements.
• Design of Biomimetic Materials: Supports creation of novel protein-based scaffolds for biomimetic material development.
• Protein Engineering for Industrial and Therapeutic Applications: Provides scaffolds for designing proteins with tailored properties for industrial and therapeutic uses.

Methodology:

Sequence-independent fragment assembly guided by specific SS assignments; sequence-independent replica-exchange Monte Carlo (REMC) simulations enhanced with multiple auxiliary movements; an energy force field including balanced SS packing terms; recognition and assembly of uncommon super-secondary structure (super-SS) geometries.