bims-lances 2025-04-13 papers

J Am Chem Soc. 2025 Apr 11.

Integrating Cryo-Electron Microscopy and Molecular Dynamics Simulations to Investigate Membrane Binding of Influenza Virus Fusion Peptides.

Piotr Setny, Paulina Borkowska, Remigiusz Worch.

We propose an approach for determining the positioning of membrane-active peptides within a lipid bilayer. It is based on a combination of cryogenic electron microscopy (cryo-EM) with molecular dynamics (MD) simulations. Cryo-EM image intensity profiles across peptide-containing liposome membranes are analyzed by comparing them to synthetic images that are derived from MD trajectories of peptide-membrane systems representing different assumed binding modes. These simulated profiles serve as baseline models, which are then used to classify experimentally obtained images into respective categories. The approach was applied to influenza virus fusion peptides, providing evidence for predominantly transmembrane binding in pure POPC membranes and a transition toward surface-bound configurations upon the addition of cholesterol.

DOI: https://doi.org/10.1021/jacs.4c18441

ArXiv. 2025 Mar 25. pii: arXiv:2303.11056v2. [Epub ahead of print]

Structure-Based Experimental Datasets for Benchmarking Protein Simulation Force Fields.

Chapin E Cavender, David A Case, Julian C-H Chen, Lillian T Chong, Daniel A Keedy, Kresten Lindorff-Larsen, David L Mobley, O H Samuli Ollila, Chris Oostenbrink, Paul Robustelli, Vincent A Voelz, Michael E Wall, David C Wych, Michael K Gilson.

This review article provides an overview of structurally oriented experimental datasets that can be used to benchmark protein force fields, focusing on data generated by nuclear magnetic resonance (NMR) spectroscopy and room temperature (RT) protein crystallography. We discuss what the observables are, what they tell us about structure and dynamics, what makes them useful for assessing force field accuracy, and how they can be connected to molecular dynamics simulations carried out using the force field one wishes to benchmark. We also touch on statistical issues that arise when comparing simulations with experiment. We hope this article will be particularly useful to computational researchers and trainees who develop, benchmark, or use protein force fields for molecular simulations.

Chemphyschem. 2025 Apr 07. e202500049

Unfolding of the Villin Headpiece Domain: Revealing Structural Heterogeneity with Time-Resolved X-ray Solution Scattering and Markov State Modeling.

Adam K Nijhawan, Arnold M Chan, Madeline B Ho, Changmin Lee, Irina Kosheleva, Lin X Chen, Kevin L Kohlstedt.

Understanding protein folding pathways is crucial to deciphering the principles of protein structure and function. Here, we investigate the unfolding dynamics of the 35-residue villin headpiece (HP35) and a norleucine-substituted variant (2F4K) using a combination of experimental and computational techniques. Time-resolved X-ray solution scattering (TRXSS) coupled with equilibrium Molecular Dynamics (MD) simulations and Markov State modeling reveals distinct unfolding mechanisms between the two variants: HP35 and 2F4K. Specifically, HP35 exhibits a two-state unfolding process, whereas an intermediate state was identified for the 2F4K mutant. A Markov state model constructed from simulations was used to map atomic-level transitions to experimental observations, providing insights into the role of sequence variations in modulating folding pathways. Our findings underscore the importance of integrating experimental and computational approaches to unravel protein unfolding mechanisms between heterogenous structural ensembles.

Keywords: Villin * TRXSS * MD * MSM * T-jump

DOI: https://doi.org/10.1002/cphc.202500049