Principles and Methods of De Novo Protein Design and Applications

Abstract

De novo protein design strategy enables to create novel protein sequence that are able to fold in stable and functional structure, while breaking through the limitation of natural evolution. This method, which is based on the idea that the amino acid sequence of a protein dictates its three-dimensional structure, identifies a particular sequence with a low-energy state by combining computational methods, molecular interaction modeling, and thermodynamic optimization. Stabilizing interactions between molecules are precisely engineered to ensure the protein is folded into desired structure, while maintaining conformational stability. Recent advanced methods in de novo protein design includes flexible and fixed backbone modeling and deep learning-guided assembly. These methods have improved accuracy of modeling and broadened available space for protein sequence. De novo protein design can be applied across multiple biomedical domains. De novo protein design achieves notable success in vaccine innovation, where stabilized epitopes are presented to enhance the immune targeting, and in immunotherapy, where synthetic cytokine mimetics achieve high selectivity with reduced toxicity. These developments demonstrate how de novo protein design is transitioning from a conceptual idea to a robust platform for advanced therapeutics.