In the last quarter-century, the field of molecular dynamics (MD) has undergone a remarkable transformation, propelled by substantial enhancements in software, hardware, and underlying methodologies. In this Perspective, we contemplate the future trajectory of MD simulations and their possible look at the year 2050. We spotlight the pivotal role of artificial intelligence (AI) in shaping the future of MD and the broader field of computational physical chemistry. We outline critical strategies and initiatives that are essential for the seamless integration of such technologies. Our discussion delves into topics like multiscale modeling, adept management of ever-increasing data deluge, the establishment of centralized simulation databases, and the autonomous refinement, cross-validation, and self-expansion of these repositories. The successful implementation of these advancements requires scientific transparency, a cautiously optimistic approach to interpreting AI-driven simulations and their analysis, and a mindset that prioritizes knowledge-motivated research alongside AI-enhanced big data exploration. While history reminds us that the trajectory of technological progress can be unpredictable, this Perspective offers guidance on preparedness and proactive measures, aiming to steer future advancements in the most beneficial and successful direction.

• Publication type
• Journal Article MeSH
• Review MeSH

Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 in silico is similar to that of voltage-dependent anion channel (VDAC), a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases.

• Keywords
• flip-flop rate, free energy barrier, hydrophilic groove, insertase, membrane defect, molecular dynamics, scramblase,
• MeSH
• Cell Membrane metabolism   MeSH
• Lipids * MeSH
• Molecular Dynamics Simulation * MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Lipids * MeSH

Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross the outer membrane to support mitochondrial function, but how they do this is unclear. We identify the Voltage Dependent Anion Channel (VDAC), an abundant outer membrane protein, as a scramblase-type lipid transporter that catalyzes lipid entry. On reconstitution into membrane vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation of phospholipids by a mechanism that is unrelated to their channel activity. Coarse-grained molecular dynamics simulations of VDAC1 reveal that lipid scrambling occurs at a specific dimer interface where polar residues induce large water defects and bilayer thinning. The rate of phospholipid import into yeast mitochondria is an order of magnitude lower in the absence of VDAC homologs, indicating that VDACs provide the main pathway for lipid entry. Thus, VDAC isoforms, members of a superfamily of beta barrel proteins, moonlight as a class of phospholipid scramblases - distinct from alpha-helical scramblase proteins - that act to import lipids into mitochondria.

• MeSH
• Phospholipids * metabolism   MeSH
• Humans MeSH
• Mitochondria metabolism   MeSH
• Voltage-Dependent Anion Channels metabolism   MeSH
• Voltage-Dependent Anion Channel 1 * metabolism   MeSH
• Saccharomyces cerevisiae metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Phospholipids * MeSH
• Voltage-Dependent Anion Channels MeSH
• Voltage-Dependent Anion Channel 1 * MeSH

Scramblases play a pivotal role in facilitating bidirectional lipid transport across cell membranes, thereby influencing lipid metabolism, membrane homeostasis, and cellular signaling. MTCH2, a mitochondrial outer membrane protein insertase, has a membrane-spanning hydrophilic groove resembling those that form the lipid transit pathway in known scramblases. Employing both coarse-grained and atomistic molecular dynamics simulations, we show that MTCH2 significantly reduces the free energy barrier for lipid movement along the groove and therefore can indeed function as a scramblase. Notably, the scrambling rate of MTCH2 in silico is similar to that of VDAC, a recently discovered scramblase of the outer mitochondrial membrane, suggesting a potential complementary physiological role for these mitochondrial proteins. Finally, our findings suggest that other insertases which possess a hydrophilic path across the membrane like MTCH2, can also function as scramblases.

• Publication type
• Journal Article MeSH
• Preprint MeSH

The precise spatiotemporal control of nanoscale membrane shape and composition is the result of a complex interplay of individual and collective molecular behaviors. Here, we employed single-molecule localization microscopy and computational simulations to observe single-lipid diffusion and sorting in model membranes with varying compositions, phases, temperatures, and curvatures. Supported lipid bilayers were created over 50-nm-radius nanoparticles to mimic the size of naturally occurring membrane buds, such as endocytic pits and the formation of viral envelopes. The curved membranes recruited liquid-disordered lipid phases while altering the diffusion and sorting of tracer lipids. Disorder-preferring fluorescent lipids sorted to and experienced faster diffusion on the nanoscale curvature only when embedded in a membrane capable of sustaining lipid phase separation at low temperatures. The curvature-induced sorting and faster diffusion even occurred when the sample temperature was above the miscibility temperature of the planar membrane, implying that the nanoscale curvature could induce phase separation in otherwise homogeneous membranes. Further confirmation and understanding of these results are provided by continuum and coarse-grained molecular dynamics simulations with explicit and spontaneous curvature-phase coupling, respectively. The curvature-induced membrane compositional heterogeneity and altered dynamics were achieved only with a coupling of the curvature with a lipid phase separation. These cross-validating results demonstrate the complex interplay of lipid phases, molecular diffusion, and nanoscale membrane curvature that are critical for membrane functionality.

• MeSH
• Cell Membrane MeSH
• Diffusion MeSH
• Lipid Bilayers * MeSH
• Molecular Dynamics Simulation * MeSH
• Temperature MeSH
• Protein Transport MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Names of Substances
• Lipid Bilayers * MeSH