Abstract
Abstract Computational models like AlphaFold2 have achieved high accuracy in protein structure prediction, but their homology search step—key to generating multiple sequence alignments (MSAs)—remains computationally expensive and prone to introducing alignment noise. We propose DIAFold, which incorporates amino acid physicochemical properties as a cost-free prefiltering strategy to improve homolog detection by prioritizing biologically meaningful MSAs over exhaustive high-sensitivity searches, using DIAMOND in a fast, single-pass setting. This yields a 5.91× speedup and reduces false positives by up to 37.7× while producing smaller yet higher-quality MSAs and preserving or improving structure prediction accuracy, particularly in low-homology regimes. These gains translate to higher TM-scores in full-chain and domain-level predictions, using fewer computational resources, highlighting the benefits of integrating physicochemical knowledge early in protein structure prediction pipelines.