Related Experiment Video
Updated: Mar 28, 2026

Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
ST-PARM: Pareto-Complete Inference-Time Alignment for Multi-Objective Protein Design
Motivation:
Protein engineering is inherently multi-objective: improving one property can degrade others, so practical workflows require generating non-dominated (Pareto-optimal) candidates spanning a trade-off surface. Linear objective scalarization and deterministic pairwise preference learning can under-explore non-convex Pareto regions and amplify noise from uncertain evaluators, limiting Pareto coverage and trade-off controllability.
Results:
We introduce Smooth Tchebycheff Preference-Aware Reward Model (ST-PARM), an inference-time alignment framework that steers a frozen protein language model along user-specified trade-offs with a lightweight reward model trained only once. ST-PARM combines (i) a reward-calibrated pairwise preference loss that is uncertainty-aware by down-weighting ambiguous comparisons under noisy evaluators, (ii) a smooth Tchebycheff scalarization that is Pareto-complete in principle and improves empirical trade-off coverage, and (iii) latent-space pair-construction strategies. On GFP fluorescence-stability (full-length design) and IL-6 nanobody stability-solubility (CDR3+suffix design), ST-PARM delivers broader Pareto coverage and stronger preference tracking than baselines PARM and MosPro. For GFP, a conservative structural screen for local confidence and global fold preservation retains a broad frontier and strong controllability, yielding an actionable cohort for downstream assays. We also provide cross-evaluator robustness checks, a three-objective extension, and a natural-language alignment generality check in the Supplement, establishing a practical foundation for controllable sequence generation under competing multi-objectives and noisy measurements.
Availability And Implementation:
https://github.com/Shen-Lab/ST-PARM .
Supplementary Information:
Supplementary data are provided with the submission.
More Related Videos
07:08Optimization of Synthetic Proteins: Identification of Interpositional Dependencies Indicating Structurally and/or Functionally Linked Residues
Published on: July 14, 2015
06:50Author Spotlight: A Computational Approach to Decipher Amino Acid Preferences in Multispecific Protein-Protein Interactions
Published on: January 26, 2024
Related Concept Videos
Protein-protein Interfaces
Conserved Binding Sites
Binding sites are often located in large pockets, and if their location on a protein’s surface is unknown, it can be predicted using various approaches. The energetic method computationally...
Conservation of Protein Domains Over Different Proteins
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
Ligand Binding and Linkage
Protein Complexes with Interchangeable Parts
Protein Complexes with Interchangeable Parts
The SCF ubiquitin ligase is a protein complex of five individual proteins. This complex attaches ubiquitin to other target proteins to mark them for degradation. In order...