AI 中文总结
ZetaDial提出采样后逐蛋白割线控制器，在推理时调节蛋白质结合剂净电荷至设定点，显著降低电荷误差，同时评估可折叠性与可开发性影响。
AI 中文摘要
净电荷是治疗性结合剂的一个与可开发性相关的性质，与黏度、清除率、非特异性相互作用和聚集有关，抗体筛选已使用电荷相关标准。然而，逆折叠流程无法将其设定为目标值。ProteinMPNN和BindCraft提供氨基酸偏好、权重选择和自定义损失，但两者均未提供逐蛋白反馈回路来测量采样后实现的电荷并将其校正至设定点。ZetaDial贡献了一个围绕固定骨架ProteinMPNN的采样后、逐蛋白割线控制器。在匹配的随机基准测试中，割线回路相对于固定斜率回路在RCSB复合物（5.17对6.46电荷单位）和Cas13单体（5.57对8.23）上将平均绝对误差降低。相对于优化的匹配全局偏置，它将RCSB误差从11.71降至5.17（聚类自助法p<0.001），且在Cas13上统计上无差异（5.47对5.57）。在800个八蛋白子集中，敏感性异质性与校准增益相关（Pearson r=0.79）；这是描述性重采样，而非前瞻性决策规则。可折叠性随偏置幅度增加而恶化。在完整的52复合物种子0分析中，参考性DockQ在±3处明显下降，但在±1.5处未下降；在八个复合物上选定的五种重复显示每个非零设置均有配对下降，但不估计所有52个复合物的效应。在探索性BindCraft扫描中，PD-L1设计在相似的最大界面pTM下趋向近中性电荷，但成功率区间重叠；IL-7R-α响应非单调，RBD未产生强设计。固定骨架C-α邻域分析发现近中性电荷处同号电荷斑块代理较小，但该代理并非实测静电表面或实验可开发性终点。
英文摘要
Net charge is a developability-relevant property of therapeutic binders, linked to viscosity, clearance, nonspecific interaction and aggregation, and antibody screens already use charge-related criteria. Yet inverse-folding pipelines expose no way to set it to a target value. ProteinMPNN and BindCraft offer amino-acid biases, weight choices and custom losses, but neither supplies a per-protein feedback loop that measures realised charge after sampling and corrects it to a setpoint. ZetaDial contributes a post-sampling, per-protein secant controller around fixed-backbone ProteinMPNN. On matched stochastic benchmarks the secant loop reduced mean absolute error relative to a fixed-slope loop on RCSB complexes (5.17 vs 6.46 charge units) and Cas13 monomers (5.57 vs 8.23). Relative to the optimised matched global bias, it cut RCSB error from 11.71 to 5.17 (cluster bootstrap p < 0.001) and was statistically indistinguishable on Cas13 (5.47 vs 5.57). Across 800 eight-protein subsets, sensitivity heterogeneity was associated with calibration gain (Pearson r = 0.79); this is descriptive resampling, not a prospective decision rule. Foldability deteriorated as bias magnitude increased. In the full 52-complex seed-0 analysis, reference-based DockQ declined clearly at +/-3 but not at +/-1.5; a selected five-seed replication on eight complexes showed paired declines at every nonzero setting, but does not estimate the effect for all 52. In exploratory BindCraft sweeps, PD-L1 designs moved toward near-neutral charge at similar maximum interface pTM but with overlapping success-rate intervals; IL-7R-alpha responses were non-monotonic and RBD produced no strong designs. A fixed-backbone C-alpha-neighbour analysis found smaller same-sign charge-patch proxies near neutral charge, but this proxy is not a measured electrostatic surface or experimental developability endpoint.
Comments14 pages, 7 figures, 2 tables
