New publication in Journal of Chemical Theory and Computation

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Mandal N, Stevens JA, Poma AB, Surpeta B, Sequeiros-Borja C, Thirunavukarasu AS, Marrink SJ, Brezovsky J, 2026: Benchmarking coarse-grained simulation methods for investigation of transport tunnels in enzymes. Journal of Chemical Theory and Computation 2026 (ASAP article) DOI:10.1021/acs.jctc.5c01727. full text dataset

Transport tunnels in enzymes with buried active sites are critical gatekeepers of enzymatic function, controlling substrate access, product release, and catalytic efficiency. Despite their importance, the transient nature of these tunnels makes them difficult to study using conventional simulation methods. In this study, we systematically evaluate three coarse-grained (CG) molecular dynamics approaches─Martini with Elastic network restraints, Martini with Go̅-model restraints, and SIRAH─for their ability to characterize tunnel structure and dynamics across diverse enzyme classes. Using haloalkane dehalogenase LinB and its engineered variants as model systems, we show that CG methods accurately reproduce the geometry of tunnel ensembles observed in all-atom (AA) simulations while providing notable computational speedups. The Martini-Go̅ model performed particularly well, capturing subtle mutation-induced changes in tunnel dynamics, such as the closure of a main tunnel and the de novo opening of a transient auxiliary tunnel in LinB variants. In contrast, Martini with Elastic network restraints was limited in capturing tunnel dynamics due to the structural bias introduced by the restraints. We further validated these findings across nine enzymes from the oxidoreductase, transferase, and hydrolase classes with diverse structural folds. Although all CG methods reliably identified functionally relevant tunnels and provided fairly accurate estimates of their ensemble geometry and key bottleneck residues, they differed in their ability to replicate tunnel dynamics, with tunnel occurrences and ranking showing moderate to good correspondence with AA results. This comprehensive evaluation highlights the strengths and weaknesses of CG simulations, establishing them as powerful tools for high-throughput analysis of enzyme tunnels, which enables more efficient enzyme engineering and drug design efforts targeting these critical structural features.

New grant awarded

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Together with our collaborators from Microbial Bioengineering Laboratory@Masaryk University, we have been successful in the recent OPUS28+LAP competition by National Science Center Poland, with project PUSH: Unlocking the unused capacity of bacterial metabolism through the rational design of substrate transporters, beating the still unfortunate 13 % success rates (hoping for better chances for all next time).

We will have openings for a Post-Doc and a doctoral student soon.

New publication in Plant Physiology

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Biała-Leonhard W, Bigos A, Brezovsky J, Jasiński M, 2025: Message hidden in α-helices – towards a better understanding of plant ABCG transporters’ multispecificity. Plant Physiology 198: kiaf146. full text

ATP-binding cassette (ABC) transporters are ubiquitous in all organisms and constitute one of the largest protein families. The substantial expansion of this family in plants coincided with the emergence of fundamental novelties that facilitated successful adaptation to a sessile lifestyle on land. It also resulted in selectivity and multispecificity toward endogenous molecules observed for certain ABC transporters. Understanding the molecular determinants behind this intriguing feature remains an ongoing challenge for the functional characterization of these proteins. This review synthesizes current achievements and methodologies that enhance our mechanistic understanding of how ABCG transporters, which are particularly numerous in land plants, specifically recognize and transport endogenous compounds. We examine in silico modeling and the recent advancements in the structural biology of ABCGs. Furthermore, we highlight internal and external factors that potentially influence the substrate selectivity of those proteins. Ultimately, this review contributes to rationalizing our current capacity to fully understand how plants orchestrate membrane transport fulfilled by these proteins.