arXiv subjects

Pavel Strashnov

Publications and source records attributed to Pavel Strashnov.

3 recordsLinked to original sources

arXiv2026

Harmonic Torsional Diffusion for Protein-Ligand Flexible Docking

Molecular docking requires reasoning jointly about ligand pose and protein flexibility. Most diffusion-based docking models predict torsional updates with generic Euclidean heads that ignore the periodic geometry of angular variables. This mismatch is especially limiting in flexible docking, where ligand conformations and pocket side chains co-adapt to form the bound complex. Here, we introduce Harmony, a harmonic torsional diffusion framework for flexible protein-ligand docking. Harmony parameterizes ligand and side-chain torsional score fields as derivatives of learned harmonic potentials on the circle, whose noise-level dependence is supplied analytically by the heat semigroup of variance-exploding diffusion on the torus. This construction makes periodicity explicit and gives the model a frequency-aware inductive bias over rotameric motion. On the PDBBind benchmark, Harmony improves ligand pose accuracy and pocket all-atom reconstruction over recent flexible docking methods. On PoseBusters, it improves the physical validity of generated complexes. Case studies on EBNA1 and KRAS G12D illustrate the method's behavior on a polar and a shallow binding site, respectively. Together, these results indicate that aligning the score parameterization with the geometry of the diffusion process is a simple and effective lever for improving flexible docking.

q-bio.BM↗

arXiv2024

Diffusion on language model encodings for protein sequence generation

Protein sequence design has seen significant advances through discrete diffusion and autoregressive approaches, yet the potential of continuous diffusion remains underexplored. Here, we present DiMA, a latent diffusion framework that operates on protein language model representations. Through systematic exploration of architectural choices and diffusion components, we develop a robust methodology that generalizes across multiple protein encoders ranging from 8M to 3B parameters. We demonstrate that our framework achieves consistently high performance across sequence-only (ESM-2, ESMc), dual-decodable (CHEAP), and multimodal (SaProt) representations using the same architecture and training approach. We extensively evaluate existing methods alongside DiMA using multiple metrics across two protein modalities, covering quality, diversity, novelty, and distribution matching of generated proteins. DiMA consistently produces novel, high-quality and diverse protein sequences and achieves strong results compared to baselines such as autoregressive, discrete diffusion and flow matching language models. The model demonstrates versatile functionality, supporting conditional generation tasks including protein family-generation, motif scaffolding and infilling, and fold-specific sequence design. This work provides a universal continuous diffusion framework for protein sequence generation, offering both architectural insights and practical applicability across various protein design scenarios. Code is released at \href{https://github.com/MeshchaninovViacheslav/DiMA}{GitHub}.

cs.LG↗

arXiv2024

FREED++: Improving RL Agents for Fragment-Based Molecule Generation by Thorough Reproduction

A rational design of new therapeutic drugs aims to find a molecular structure with desired biological functionality, e.g., an ability to activate or suppress a specific protein via binding to it. Molecular docking is a common technique for evaluating protein-molecule interactions. Recently, Reinforcement Learning (RL) has emerged as a promising approach to generating molecules with the docking score (DS) as a reward. In this work, we reproduce, scrutinize and improve the recent RL model for molecule generation called FREED (arXiv:2110.01219). Extensive evaluation of the proposed method reveals several limitations and challenges despite the outstanding results reported for three target proteins. Our contributions include fixing numerous implementation bugs and simplifying the model while increasing its quality, significantly extending experiments, and conducting an accurate comparison with current state-of-the-art methods for protein-conditioned molecule generation. We show that the resulting fixed model is capable of producing molecules with superior docking scores compared to alternative approaches.

q-bio.BM↗