Addressing these challenges requires scale. To that end we introduce ProteinGym, a large-scale and holistic set of benchmarks specifically designed for protein fitness prediction and design.

Nucleotide sequence variation can induce significant shifts in functional fitness. Recent nucleotide foundation models promise to predict such fitness effects directly from sequence, yet heterogeneous datasets and inconsistent preprocessing make it difficult to compare methods fairly across DNA and RNA families. Here we introduce NABench, a large-scale, systematic benchmark for nucleic acid fitness prediction. NABench aggregates 162 high-throughput assays and curates 2.6 million mutated sequences spanning diverse DNA and RNA families, with standardized splits and rich metadata. We show that NABench surpasses prior nucleotide fitness benchmarks in scale, diversity, and data quality. Under a unified evaluation suite, we rigorously assess 29 representative foundation models across zero-shot, few-shot prediction, transfer learning, and supervised settings. The results quantify performance heterogeneity across tasks and nucleic-acid types, demonstrating clear strengths and failure modes for different modeling choices and establishing strong, reproducible baselines. We release NABench to advance nucleic acid modeling, supporting downstream applications in RNA/DNA design, synthetic biology, and biochemistry. Our code is available at https://github.com/mrzzmrzz/NABench.

Machine learning models increasingly map biological sequence-fitness landscapes to predict mutational effects. Effective evaluation of these models requires benchmarks curated from empirical data. Despite their impressive scales, existing benchmarks lack topographical information regarding the underlying fitness landscapes, which hampers interpretation and comparison of model performance beyond averaged scores. Here, we introduce GraphFLA, a Python framework that constructs and analyzes fitness landscapes from mutagensis data in diverse modalities (e.g., DNA, RNA, protein, and beyond) with up to millions of mutants. GraphFLA calculates 20 biologically relevant features that characterize 4 fundamental aspects of landscape topography. By applying GraphFLA to over 5,300 landscapes from ProteinGym, RNAGym, and CIS-BP, we demonstrate its utility in interpreting and comparing the performance of dozens of fitness prediction models, highlighting factors influencing model accuracy and respective advantages of different models. In addition, we release 155 combinatorially complete empirical fitness landscapes, encompassing over 2.2 million sequences across various modalities. All the codes and datasets are available at https://github.com/COLA-Laboratory/GraphFLA.

Designing protein sequences of both high fitness and novelty is a challenging task in data-efficient protein engineering. Exploration beyond wild-type neighborhoods often leads to biologically implausible sequences or relies on surrogate models that lose fidelity in novel regions. Here, we propose ProSpero, an active learning framework in which a frozen pre-trained generative model is guided by a surrogate updated from oracle feedback. By integrating fitness-relevant residue selection with biologically-constrained Sequential Monte Carlo sampling, our approach enables exploration beyond wild-type neighborhoods while preserving biological plausibility. We show that our framework remains effective even when the surrogate is misspecified. ProSpero consistently outperforms or matches existing methods across diverse protein engineering tasks, retrieving sequences of both high fitness and novelty.

Protein optimization is a fundamental biological task aimed at enhancing the performance of proteins by modifying their sequences. Computational methods primarily rely on evolutionary information (EI) encoded by protein language models (PLMs) to predict fitness landscape for optimization. However, these methods suffer from a few limitations.

Understanding the consequences of mutation for molecular fitness and function is a fundamental problem in biology.

Understanding the relationships between objectives in a multiobjective optimisation problem is important for developing tailored and efficient solving techniques. In particular, when tackling combinatorial optimisation problems with many objectives, that arise in real-world logistic scenarios, better support for the decision maker can be achieved through better understanding of the often complex fitness landscape. This paper makes a contribution in this direction by presenting a technique that allows a visualisation and analysis of the local and global relationships between objectives in optimisation problems with many objectives. The proposed technique uses four steps: First, the global pairwise relationships are analysed using the Kendall correlation method; then, the ranges of the values found on the given Pareto front are estimated and assessed; next, these ranges are used to plot a map using Gray code, similar to Karnaugh maps, that has the ability to highlight the trade-offs between multiple objectives; and finally, local relationships are identified using scatter plots. Experiments are presented for three combinatorial optimisation problems: multiobjective multidimensional knapsack problem, multiobjective nurse scheduling problem, and multiobjective vehicle routing problem with time windows . Results show that the proposed technique helps in the gaining of insights into the problem difficulty arising from the relationships between objectives.