AntiBMPNN: Structure‐Guided Graph Neural Networks for Precision Antibody Engineering

Abstract Antibodies are crucial for medical applications, yet traditional methods for designing sequences are inefficient. This study introduces AntiBMPNN, an advanced deep‐learning framework that leverages an antibody‐specific 3D dataset, a fine‐tuned message‐passing neural network (MPNN), a frequency‐based scoring function, and AlphaFold 3 to achieve highly accurate antibody sequence design. AntiBMPNN surpasses ProteinMPNN with a perplexity of 1.5 and over 80% sequence recovery. Its scoring function, combined with AlphaFold 3, effectively prioritizes sequences based on structural recovery, positional stability, and biochemical or complex properties. Experimental validation highlights a 75% success rate in single‐point antibody design. AntiBMPNN consistently outperforms AbMPNN, AntiFold, and ProteinMPNN in designing complementarity determining regions (CDR) 1‐3, yielding stronger binding affinities. For CDR1 of huJ3 (anti‐HIV nanobody), it achieves a half maximal effective concentration (EC₅₀) of 9.2 nM (nanomolar), better than ProteinMPNN (135.2 nM) and AntiFold (59.3 nM), and comparable to AbMPNN (6.6 nM). For CDR2 of the D6 nanobody (targeting CD16), AntiBMPNN reaches 0.3 nM, outperforming AbMPNN (2.3 nM), AntiFold (0.7 nM), and ProteinMPNN (0.7 nM). In CDR3 of huJ3, it achieves 1.7 nM, surpassing AbMPNN (51.2 nM), with no detectable activity from AntiFold or ProteinMPNN. These findings confirm that AntiBMPNN‐designed sequences for J3 and D6 outperform the originals, highlighting its potential to improve therapeutic antibody design.