The Laboratoire International Associé between the Centre National de la Recherche Scientifique and the University of Illinois at Urbana-Champaign was launched at the end of 2012. Its primary objective is to develop methods for high-performance molecular simulation with the aim of understanding the function of complex biological assemblies, transcending the frontiers of traditional disciplines by uniting mathematicians, physicists, theoretical chemists and biologists on both sides of the Atlantic. In France, the major contributors are located at the Université de Lorraine, the École des Ponts ParisTech, the Institut de Biologie Structurale and the Laboratoire de Biologie Physico-Chimique. In the United States, the contributors belong to the NIH Resource for Macromolecular Modeling and Bioinformatics. In Nancy, the partner is a theoretical chemistry and biophysics group incepted in 2003. Its expertise lies in describing the structure and the dynamic properties of the biological membrane and elucidating the mechanisms of the cell machinery. To attain this goal, its members leverage numerical simulations over size and timescales commensurate with the biological process at hand. Over the years, the team has gleaned milestone results in such diverse research areas as membrane transport, interaction with the biological membrane, membrane protein structure and function, as well as self-organized molecular systems. They also develop original approaches in the field of free-energy calculations to tackle rare events in biology.
Highlight
Perforin-2 clockwise hand-over-hand pre-pore to pore transition mechanism. Perforin-2 (PFN2, MPEG1) is a pore-forming protein that acts as a first line of defense in the mammalian immune system, rapidly killing engulfed microbes within the phagolysosome in macrophages. PFN2 self-assembles into hexadecameric pre-pore rings that transition upon acidification into pores damaging target cell membranes. Here, using high-speed atomic force microscopy (HS-AFM) imaging and line-scanning and molecular dynamics simulation, we elucidate PFN2 pre-pore to pore transition pathways and dynamics. Upon acidification, the pre-pore rings (pre-pore-I) display frequent, 1.8 s−1, ring-opening dynamics that eventually, 0.2 s−1, initiate transition into an intermediate, short-lived, ~75 ms, pre-pore-II state, inducing a clockwise prepore-I to pre-pore-II propagation. Concomitantly, the first pre-pore-II subunit, undergoes a major conformational change to the pore state that propagates also clockwise at a rate ~15 s−1. Thus, the pre-pore to pore transition is a clockwise hand-over-hand mechanism that is accomplished within ~1.3 s. Our findings suggest a clockwise mechanism of membrane insertion that with variations may be general for the MACPF/CDC superfamily. Nature Communications, 2022.
Recent publications
Free Energy Methods for the Description of Molecular Processes
Christophe Chipot;
Annual Review of Biophysics (2023) 52 (1):
A Practical Guide to Recent Advances in Multiscale Modeling and Simulation of BiomoleculesEnhanced Sampling Based on Collective Variables
Yong Wang; Ruhong Zhou; Haohao Fu; Wensheng Cai; Christophe Chipot; Xueguang Shao; (2023) 1-22
Chasing collective variables using temporal data-driven strategies
Haochuan Chen; Christophe Chipot;
QRB Discovery (2023) 413 (242-
