TCM Four-Qi (Si Qi) Geometric Validation: TPSA as the Primary Molecular Descriptor for Hot/Cold Drug Classification and a Three-Layer Architecture for Thermal Property Prediction

The Four-Qi (Si Qi: Hot, Warm, Neutral, Cool, Cold) classification of TCM drugs has been treated as experiential for millennia. This paper provides the first geometric validation within the Lo-Shu Projection (LSP) framework. Among 15 clean small-molecule TCM active compounds (MW<=400), TPSA (topological polar surface area) significantly separates Hot/Warm from Cold/Cool drugs (Yang mean=40. 3 A2 vs Yin mean=76. 7 A2, Mann-Whitney p=0. 045*, Cohen's d=-1. 03; Spearman rho=-0. 514*). By contrast, Lo-Shu descriptors QLTE and GII do NOT separate Four-Qi nature (p=ns), establishing that thermal property operates at the molecular absorption layer (Layer 1), not the protein-target geometry layer (Layer 2). A three-layer architecture is proposed: Layer 1 (TPSA, molecular polarity) encodes thermal character; Layer 2 (QLTE x GII, Lo-Shu geometry) encodes mechanism selectivity; Layer 3 (lambda2 x Windkessel) encodes pulse waveform response. The Berberine anomaly (Cold nature, low TPSA=40) demonstrates that target-specific mechanism can override molecular polarity prediction, defining a two-mechanism rule for Four-Qi classification. Part of the Genesis Geometric Medicine Framework v4 series.