bims-lances 2024-12-15 papers

Angew Chem Int Ed Engl. 2024 Dec 07. e202417804

Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions.

Fabian Schuhmann, Kerem Can Akkaya, Dmytro Puchkov, Martin Lehmann, Fan Liu, Weria Pezeshkian.

Cross-linking mass spectrometry (XL-MS) enables the mapping of protein-protein interactions on the cellular level. When applied to all compartments of mitochondria, the sheer number of cross-links and connections can be overwhelming, rendering simple cluster analyses convoluted and uninformative. To address this limitation, we integrate the XL-MS data, 3D electron microscopy data, and localization annotations with a supra coarse-grained molecular dynamics simulation to sort all data, making clusters more accessible and interpretable. In the context of mitochondria, this method, through a total of 6.9 milliseconds of simulations, successfully identifies known, suggests unknown protein clusters, and reveals the distribution of inner mitochondrial membrane proteins allowing a more precise localization within compartments. Our integrative approach suggests, that two so-far ambigiously placed proteins FAM162A and TMEM126A are localized in the cristae, which is validated through super resolution microscopy. Together, this demonstrates the strong potential of the presented approach.

Keywords: 3D volumetric imaging; Cross-linking mass spectrometry; Molecular Dynamics; mitochondrial protein distribution; supra coarse-grained

DOI: https://doi.org/10.1002/anie.202417804

J Chem Theory Comput. 2024 Dec 12.

Extended Sampling of Macromolecular Conformations from Uniformly Distributed Points on Multidimensional Normal Mode Hyperspheres.

Antoniel A S Gomes, Mauricio G S Costa, Maxime Louet, Nicolas Floquet, Paulo M Bisch, David Perahia.

Proteins are dynamic entities that adopt diverse conformations, which play a pivotal role in their function. Understanding these conformations is essential, and protein collective motions, particularly those captured by normal mode (NM) and their linear combinations, provide a robust means for conformational sampling. This work introduces a novel approach to obtaining a uniformly oriented set of a given number of lowest frequency NM combined vectors and generating harmonically equidistant restrained structures along them. They are all thus uniformly located on concentric hyperspheres, systematically covering the defined NM space fully. The generated structures are further relaxed with standard molecular dynamics (MD) simulations to explore the conformational space. The efficiency of the approach we termed "distributed points Molecular Dynamics using Normal Modes" (dpMDNM) was assessed by applying it to hen egg-white lysozyme and human cytochrome P450 3A4 (CYP3A4). To this purpose, we compared our new approach with other methods and analyzed the sampling of existing experimental structures. Our results demonstrate the efficacy of dpMDNM in extensive conformational sampling, particularly as more NMs are considered. Ensembles generated by dpMDNM exhibited a broad coverage of the experimental structures, providing valuable insights into the functional aspects of lysozyme and CYP3A4. Furthermore, dpMDNM also covered lysozyme structures with relatively elevated energies corresponding to transient states not easily obtained by standard MD simulations, in conformity with nuclear magnetic resonance structural indications. This method offers an efficient and rational framework for comprehensive protein conformational sampling, contributing significantly to our understanding of protein dynamics and function.

DOI: https://doi.org/10.1021/acs.jctc.4c01054

J Chem Phys. 2024 Dec 14. pii: 224106. [Epub ahead of print]161(22):

Integrating path sampling with enhanced sampling for rare-event kinetics.

Dhiman Ray.

Studying the kinetics of long-timescale rare events is a fundamental challenge in molecular simulation. To address this problem, we propose an integration of two different rare-event sampling philosophies: biased enhanced sampling and unbiased path sampling. Enhanced sampling methods, e.g., metadynamics, can facilitate the crossing of free energy barriers by applying an external bias potential. On the contrary, path sampling methods like weighted ensemble do not apply any biasing force but accelerate the exploration of rugged free energy surfaces through trajectory resampling. We show that a judicious combination of the weighted ensemble with a metadynamics-like algorithm can synergize the strengths and mitigate the deficiencies of path sampling and enhanced sampling approaches. The resulting integrated sampling (IS) algorithm improves the computational efficiency of calculating the kinetics of peptide conformational transitions, protein unfolding, and the dissociation of a ligand-receptor complex. Furthermore, the IS approach can direct sampling along the minimum free energy pathway even when the collective variable used for biasing is suboptimal. These advantages make the IS algorithm suitable for studying the kinetics of complex molecular systems of biological and pharmaceutical relevance.

DOI: https://doi.org/10.1063/5.0239303