Rigidity-Aware Geometric Pretraining for Protein Design and Conformational Ensembles

TL;DR

This paper introduces RigidSSL, a geometric pretraining framework for protein design that learns global structural priors and conformational dynamics, significantly improving generative modeling and downstream tasks.

Contribution

The paper presents RigidSSL, a novel two-phase geometric pretraining method that jointly models protein structure and dynamics, addressing limitations of local representations and static modeling.

Findings

Improves designability by up to 43% in protein generation

Enhances success rate by 5.8% in zero-shot motif scaffolding

Captures realistic conformational ensembles in GPCR modeling

Abstract

Generative models have recently advanced $\textit{de novo}$ protein design by learning the statistical regularities of natural structures. However, current approaches face three key limitations: (1) Existing methods cannot jointly learn protein geometry and design tasks, where pretraining can be a solution; (2) Current pretraining methods mostly rely on local, non-rigid atomic representations for property prediction downstream tasks, limiting global geometric understanding for protein generation tasks; and (3) Existing approaches have yet to effectively model the rich dynamic and conformational information of protein structures. To overcome these issues, we introduce $\textbf{RigidSSL}$ ($\textit{Rigidity-Aware Self-Supervised Learning}$), a geometric pretraining framework that front-loads geometry learning prior to generative finetuning. Phase I (RigidSSL-Perturb) learns geometric priors from 432K structures from the AlphaFold Protein Structure Database with simulated perturbations. Phase II (RigidSSL-MD) refines these representations on 1.3K molecular dynamics trajectories to capture physically realistic transitions. Underpinning both phases is a bi-directional, rigidity-aware flow matching objective that jointly optimizes translational and rotational dynamics to maximize mutual information between conformations. Empirically, RigidSSL variants improve designability by up to 43% while enhancing novelty and diversity in unconditional generation. Furthermore, RigidSSL-Perturb improves the success rate by 5.8% in zero-shot motif scaffolding and RigidSSL-MD captures more biophysically realistic conformational ensembles in G protein-coupled receptor modeling.