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1. Molecular Dynamics to Predict Cryo-EM: Capturing Transitions and Short-Lived Conformational States of Biomolecules

   https://doi.org/10.3389/fmolb.2021.641208  

   Nierzwicki, Łukasz; Palermo, Giulia (April 2021, Frontiers in Molecular Biosciences)

   null (Ed.)

   Single-particle cryogenic electron microscopy (cryo-EM) has revolutionized the field of the structural biology, providing an access to the atomic resolution structures of large biomolecular complexes in their near-native environment. Today’s cryo-EM maps can frequently reach the atomic-level resolution, while often containing a range of resolutions, with conformationally variable regions obtained at 6 Å or worse. Low resolution density maps obtained for protein flexible domains, as well as the ensemble of coexisting conformational states arising from cryo-EM, poses new challenges and opportunities for Molecular Dynamics (MD) simulations. With the ability to describe the biomolecular dynamics at the atomic level, MD can extend the capabilities of cryo-EM, capturing the conformational variability and predicting biologically relevant short-lived conformational states. Here, we report about the state-of-the-art MD procedures that are currently used to refine, reconstruct and interpret cryo-EM maps. We show the capability of MD to predict short-lived conformational states, finding remarkable confirmation by cryo-EM structures subsequently solved. This has been the case of the CRISPR-Cas9 genome editing machinery, whose catalytically active structure has been predicted through both long-time scale MD and enhanced sampling techniques 2 years earlier than cryo-EM. In summary, this contribution remarks the ability of MD to complement cryo-EM, describing conformational landscapes and relating structural transitions to function, ultimately discerning relevant short-lived conformational states and providing mechanistic knowledge of biological function. 

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2. Mapping the structural–mechanical landscape of amorphous carbon with ReaxFF molecular dynamics

   https://doi.org/10.1063/5.0246126  

   Dernov, A; Kowalik, M; van_Duin, A_C T; Dumitrică, T (February 2025, Journal of Applied Physics)

   We use ReaxFF molecular dynamics (MD) to investigate the relationship between structural and mechanical properties in bulk and nanostructured amorphous carbon (a-C). The liquid-quench MD method is used to generate isotropic bulk samples with mass densities ranging from 0.96 to 3.29 g/cm3. Structural analysis identifies two types of structures with distinct short- and medium-range order: lower-density sp2-dominated a-C, which is characterized by a bimodal ring-size distribution, and higher-density sp3-dominated tetrahedral amorphous carbon (ta-C), exhibiting a unimodal ring-size distribution. Stress–strain MD simulations and analysis reveal how an atomistic structure impacts elastic properties and post-yield atomic rearrangements. All stretched structures demonstrate elastic isotropy and plasticity driven by a ring-size expansion mechanism reflected in changes in ring statistics. The plastic region is substantially larger in ta-C than in a-C due to the post-yield shift from sp3 to sp2 C dominant bonding. In both a-C and ta-C, ultimate failure occurs when a reactive crack, traversed by long sp chains, forms and propagates predominantly perpendicular to the direction of the applied strain. Oxygen infiltration into the fractured region significantly reduces stress resistance, primarily through the early rupture of long sp chains. MD simulations and analysis are extended to a-C slabs, a-C nanotubes, and partially a-C nanotubes. The latter nanostructure highlights the differences between the elastically isotropic a-C walls, which develop circumferential cracking, and the crystalline walls, which tear along crystallographic directions. These results provide a strong foundation for further computational characterization of a-C materials. 

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3. Effects of elevated-temperature deposition on the atomic structure of amorphous Ta2O5 films

   https://doi.org/10.1063/5.0170100  

    Prasai, K.; Lee, K.; Baloukas, B.;  Cheng, H-P; Fazio, M.; Martinu, L.; Mehta, A.; Menoni, C_S; Schiettekatte, F.; Shink, R.; et al (December 2023, APL Materials)

   Brownian thermal noise as a result of mechanical loss in optical coatings will become the dominant source of noise at the most sensitive frequencies of ground-based gravitational-wave detectors. Experiments found, however, that a candidate material, amorphous Ta2O5, is unable to form an ultrastable glass and, consequently, to yield a film with significantly reduced mechanical loss through elevated-temperature deposition alone. X-ray scattering PDF measurements are carried out on films deposited and subsequently annealed at various temperatures. Inverse atomic modeling is used to analyze the short and medium range features in the atomic structure of these films. Furthermore, in silico deposition simulations of Ta2O5 are carried out at various substrate temperatures and an atomic level analysis of the growth at high temperatures is presented. It is observed that upon elevated-temperature deposition, short range features remain identical, whereas medium range order increases. After annealing, however, both the short and medium range orders of films deposited at different substrate temperatures are nearly identical. A discussion on the surface diffusion and glass transition temperatures indicates that future pursuits of ultrastable low-mechanical-loss films through elevated temperature deposition should focus on materials with a high surface mobility, and/or lower glass transition temperatures in the range of achievable deposition temperatueres. 

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4. Impact of Replicas and Simulation Length on In Silico Behaviors of a Protein Domain

   https://doi.org/10.1002/cphc.202400783  

   Biswas, Arumay; Eisert‐Sasse, Riley K; Okafor, C Denise (February 2025, ChemPhysChem)

   Abstract Molecular dynamics (MD) simulations are immensely valuable for studying protein structure, function and dynamics. Their ability to capture atomic‐level behavior of molecules and describe their evolution over time makes it a powerful synergistic tool for biochemistry, structural biology and other life sciences. To advance research and knowledge on reasonable timescales, researchers must optimize the amount of useful information extracted from simulation data while often frugally managing computational resources. Often, this involves balancing the length of MD trajectories with the number of replicas of a given system, with the aim of maximizing sampling of the conformational landscape. However, identifying this balance is not always intuitive, and the lack of standards among researchers can produce large variability in results and predictions from MD measurements. Here, we investigate the variability in MD results when simulation length and replica numbers are varied. Using a 231‐amino acid domain, we compare measurements from independent trajectories to a benchmark trajectory of 3, 1000‐ns replicates. We perform these simulations on 27 protein‐ligand complexes, allowing us to compare ligand‐specific rankings of complexes across independent replicas. Our results reveal that some MD measurements are accurately ranked by single trajectories, while others are not. We uncover similar variability in the effects of trajectory lengths on measurements. Our findings suggest that a one‐size‐fits‐all approach to MD simulations is not necessarily the best approach, and depending on the intended measurements and research question, it may be advantageous sometimes to prioritize longer trajectories over multiple replicas. This work provides important considerations for researchers while designing simulation studies. 

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5. Orientation and dynamics of Cu ²⁺ based DNA labels from force field parameterized MD elucidates the relationship between EPR distance constraints and DNA backbone distances

   https://doi.org/10.1039/d0cp05016d  

   Ghosh, Shreya; Casto, Joshua; Bogetti, Xiaowei; Arora, Charu; Wang, Junmei; Saxena, Sunil (December 2020, Physical Chemistry Chemical Physics)

   null (Ed.)

   Pulsed electron paramagnetic resonance (EPR) based distance measurements using the recently developed Cu 2+ -DPA label present a promising strategy for measuring DNA backbone distance constraints. Herein we develop force field parameters for Cu 2+ -DPA in order to understand the features of this label at an atomic level. We perform molecular dynamics (MD) simulations using the force field parameters of Cu 2+ -DPA on four different DNA duplexes. The distance between the Cu 2+ centers, extracted from the 2 μs MD trajectories, agrees well with the experimental distance for all the duplexes. Further analyses of the trajectory provide insight into the orientation of the Cu 2+ -DPA inside the duplex that leads to such agreement with experiments. The MD results also illustrate the ability of the Cu 2+ -DPA to report on the DNA backbone distance constraints. Furthermore, measurement of fluctuations of individual residues showed that the flexibility of Cu 2+ -DPA in a DNA depends on the position of the label in the duplex, and a 2 μs MD simulation is not sufficient to fully capture the experimental distribution in some cases. Finally, the MD trajectories were utilized to understand the key aspects of the double electron electron resonance (DEER) results. The lack of orientational selectivity effects of the Cu 2+ -DPA at Q-band frequency is rationalized in terms of fluctuations in the Cu 2+ coordination environment and rotameric fluctuations of the label linker. Overall, a combination of EPR and MD simulations based on the Cu 2+ -DPA labelling strategy can contribute towards understanding changes in DNA backbone conformations during protein–DNA interactions. 

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