arXiv subjects

Stanislav Mazurenko

Publications and source records attributed to Stanislav Mazurenko.

8 recordsLinked to original sources

arXiv2025

Generalization Beyond Benchmarks: Evaluating Learnable Protein-Ligand Scoring Functions on Unseen Targets

As machine learning becomes increasingly central to molecular design, it is vital to ensure the reliability of learnable protein-ligand scoring functions on novel protein targets. While many scoring functions perform well on standard benchmarks, their ability to generalize beyond training data remains a significant challenge. In this work, we evaluate the generalization capability of state-of-the-art scoring functions on dataset splits that simulate evaluation on targets with a limited number of known structures and experimental affinity measurements. Our analysis reveals that the commonly used benchmarks do not reflect the true challenge of generalizing to novel targets. We also investigate whether large-scale self-supervised pretraining can bridge this generalization gap and we provide preliminary evidence of its potential. Furthermore, we probe the efficacy of simple methods that leverage limited test-target data to improve scoring function performance. Our findings underscore the need for more rigorous evaluation protocols and offer practical guidance for designing scoring functions with predictive power extending to novel protein targets.

cs.LG↗

arXiv2025

Learning to engineer protein flexibility

Generative machine learning models are increasingly being used to design novel proteins for therapeutic and biotechnological applications. However, the current methods mostly focus on the design of proteins with a fixed backbone structure, which leads to their limited ability to account for protein flexibility, one of the crucial properties for protein function. Learning to engineer protein flexibility is problematic because the available data are scarce, heterogeneous, and costly to obtain using computational as well as experimental methods. Our contributions to address this problem are three-fold. First, we comprehensively compare methods for quantifying protein flexibility and identify data relevant to learning. Second, we design and train flexibility predictors utilizing sequential or both sequential and structural information on the input. We overcome the data scarcity issue by leveraging a pre-trained protein language model. Third, we introduce a method for fine-tuning a protein inverse folding model to steer it toward desired flexibility in specified regions. We demonstrate that our method Flexpert-Design enables guidance of inverse folding models toward increased flexibility. This opens up new possibilities for protein flexibility engineering and the development of proteins with enhanced biological activities.

q-bio.BM↗

arXiv2024

DOME Registry: Implementing community-wide recommendations for reporting supervised machine learning in biology

Supervised machine learning (ML) is used extensively in biology and deserves closer scrutiny. The DOME recommendations aim to enhance the validation and reproducibility of ML research by establishing standards for key aspects such as data handling and processing, optimization, evaluation, and model interpretability. The recommendations help to ensure that key details are reported transparently by providing a structured set of questions. Here, we introduce the DOME Registry (URL: registry.dome-ml.org), a database that allows scientists to manage and access comprehensive DOME-related information on published ML studies. The registry uses external resources like ORCID, APICURON and the Data Stewardship Wizard to streamline the annotation process and ensure comprehensive documentation. By assigning unique identifiers and DOME scores to publications, the registry fosters a standardized evaluation of ML methods. Future plans include continuing to grow the registry through community curation, improving the DOME score definition and encouraging publishers to adopt DOME standards, promoting transparency and reproducibility of ML in the life sciences.

q-bio.OT↗

arXiv2024

Revealing data leakage in protein interaction benchmarks

In recent years, there has been remarkable progress in machine learning for protein-protein interactions. However, prior work has predominantly focused on improving learning algorithms, with less attention paid to evaluation strategies and data preparation. Here, we demonstrate that further development of machine learning methods may be hindered by the quality of existing train-test splits. Specifically, we find that commonly used splitting strategies for protein complexes, based on protein sequence or metadata similarity, introduce major data leakage. This may result in overoptimistic evaluation of generalization, as well as unfair benchmarking of the models, biased towards assessing their overfitting capacity rather than practical utility. To overcome the data leakage, we recommend constructing data splits based on 3D structural similarity of protein-protein interfaces and suggest corresponding algorithms. We believe that addressing the data leakage problem is critical for further progress in this research area.

cs.LG↗

arXiv2024

Learning to design protein-protein interactions with enhanced generalization

Discovering mutations enhancing protein-protein interactions (PPIs) is critical for advancing biomedical research and developing improved therapeutics. While machine learning approaches have substantially advanced the field, they often struggle to generalize beyond training data in practical scenarios. The contributions of this work are three-fold. First, we construct PPIRef, the largest and non-redundant dataset of 3D protein-protein interactions, enabling effective large-scale learning. Second, we leverage the PPIRef dataset to pre-train PPIformer, a new SE(3)-equivariant model generalizing across diverse protein-binder variants. We fine-tune PPIformer to predict effects of mutations on protein-protein interactions via a thermodynamically motivated adjustment of the pre-training loss function. Finally, we demonstrate the enhanced generalization of our new PPIformer approach by outperforming other state-of-the-art methods on new, non-leaking splits of standard labeled PPI mutational data and independent case studies optimizing a human antibody against SARS-CoV-2 and increasing the thrombolytic activity of staphylokinase.

cs.LG↗

arXiv2020

Primal-dual block-proximal splitting for a class of non-convex problems

We develop block structure adapted primal-dual algorithms for non-convex non-smooth optimisation problems whose objectives can be written as compositions $G(x)+F(K(x))$ of non-smooth block-separable convex functions $G$ and $F$ with a non-linear Lipschitz-differentiable operator $K$. Our methods are refinements of the non-linear primal-dual proximal splitting method for such problems without the block structure, which itself is based on the primal-dual proximal splitting method of Chambolle and Pock for convex problems. We propose individual step length parameters and acceleration rules for each of the primal and dual blocks of the problem. This allows them to convergence faster by adapting to the structure of the problem. For the squared distance of the iterates to a critical point, we show local $O(1/N)$, $O(1/N^2)$ and linear rates under varying conditions and choices of the step lengths parameters. Finally, we demonstrate the performance of the methods on practical inverse problems: diffusion tensor imaging and electrical impedance tomography.

math.OC↗

arXiv2020

Primal-dual proximal splitting and generalized conjugation in non-smooth non-convex optimization

We demonstrate that difficult non-convex non-smooth optimization problems, such as Nash equilibrium problems and anisotropic as well as isotropic Potts segmentation model, can be written in terms of generalized conjugates of convex functionals. These, in turn, can be formulated as saddle-point problems involving convex non-smooth functionals and a general smooth but non-bilinear coupling term. We then show through detailed convergence analysis that a conceptually straightforward extension of the primal--dual proximal splitting method of Chambolle and Pock is applicable to the solution of such problems. Under sufficient local strong convexity assumptions of the functionals -- but still with a non-bilinear coupling term -- we even demonstrate local linear convergence of the method. We illustrate these theoretical results numerically on the aforementioned example problems.

math.OC↗

arXiv2018

Acceleration and global convergence of a first-order primal--dual method for nonconvex problems

The primal--dual hybrid gradient method (PDHGM, also known as the Chambolle--Pock method) has proved very successful for convex optimization problems involving linear operators arising in image processing and inverse problems. In this paper, we analyze an extension to nonconvex problems that arise if the operator is nonlinear. Based on the idea of testing, we derive new step length parameter conditions for the convergence in infinite-dimensional Hilbert spaces and provide acceleration rules for suitably (locally and/or partially) monotone problems. Importantly, we prove linear convergence rates as well as global convergence in certain cases. We demonstrate the efficacy of these step length rules for PDE-constrained optimization problems.

math.OC↗