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At least 415 records · Page 23
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Alchemical Free Energy Estimators and Molecular Dynamics Engines: Accuracy, Precision, and Reproducibility

The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat a myriad of diseases. In this work, we examine the computation of alchemical relative binding free energies with an eye for assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2, and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2, and NAMD3 alpha. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between them of 0.50 kcal/mol. The correlation between packages is very good, with the lowest Spearman’s, Pearson’s and Kendall’s tau correlation coefficients being 0.92, 0.91, and 0.76, respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Molecular level insight into non-bilayer structure formation in thylakoid membranes: a molecular dynamics study

In oxygenic photosynthetic organisms, the light reactions are performed by protein complexes embedded in the lipid bilayer of thylakoid membranes (TMs). The organization of the bulk lipid molecules into bilayer structures provide optimal conditions for the build-up of the proton motive force (pmf) and its utilization for ATP synthesis. However, the lipid composition of TMs is dominated by the non-bilayer lipid species monogalactosyl diacylglycerol (MGDG), and functional plant TMs, besides the bilayer, contain large amounts of non-bilayer lipid phases. Bulk lipids have been shown to be associated with lumenal, stromal-side and marginal-region proteins and proposed to play roles in the self-assembly and photoprotection of the photosynthetic machinery. Furthermore, it has recently been pointed out that the generation and utilization of pmf for ATP synthesis according to the ‘protet’ or protonic charge transfer model Kell (Biochim Biophys Acta Bioenerg 1865(4):149504, 2024), requires high MGDG content Garab (Physiol Plant 177(2):e70230, 2025). In this study, to gain better insight into the structural and functional roles of MGDG, we employed all atom and coarse-grained molecular dynamics simulations to explore how temperature, hydration levels and varying MGDG concentrations affect the structural and dynamic properties of bilayer membranes constituted of plant thylakoid lipids. Our findings reveal that MGDG promotes increased membrane fluidity and dynamic fluctuations in membrane thickness. MGDG-rich stacked bilayers spontaneously formed inverted hexagonal phases; these transitions were enhanced at low hydration levels and at elevated but physiologically relevant temperatures. It can thus be inferred that MGDG plays important roles in heat and drought stress mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Understanding interactions between biomolecules and two-dimensional nanomaterials using in silico microscopes

We report two-dimensional (2D) nanomaterials such as graphene are increasingly used in research and industry for various biomedical applications. Extensive experimental and theoretical studies have revealed that 2D nanomaterials are promising drug delivery vehicles, yet certain materials exhibit toxicity under biological conditions. So far, it is known that 2D nanomaterials possess strong adsorption propensities for biomolecules. To mitigate potential toxicity and retain favorable physical and chemical properties of 2D nanomaterials, it is necessary to explore the underlying mechanisms of interactions between biomolecules and nanomaterials for the subsequent design of biocompatible 2D nanomaterials for nanomedicine. The purpose of this review is to integrate experimental findings with theoretical observations and facilitate the study of 2D nanomaterial interaction with biomolecules at the molecular level. We discuss the current understanding and progress of 2D nanomaterial interaction with proteins, lipid membranes, and DNA based on molecular dynamics (MD) simulation. In this review, we focus on the 2D graphene nanosheet and briefly discuss other 2D nanomaterials. With the ever-growing computing power, we can image nanoscale processes using MD simulation that are otherwise not observable in experiment. We expect that molecular characterization of the complex behavior between 2D nanomaterials and biomolecules will help fulfill the goal of designing effective 2D nanomaterials as drug delivery platforms.

2D nanomaterials↗
DOE OSTI2020

Protein folding from heterogeneous unfolded state revealed by time-resolved X-ray solution scattering

One of the most challenging tasks in biological science is to understand how a protein folds. In theoretical studies, the hypothesis adopting a funnel-like free-energy landscape has been recognized as a prominent scheme for explaining protein folding in views of both internal energy and conformational heterogeneity of a protein. Despite numerous experimental efforts, however, comprehensively studying protein folding with respect to its global conformational changes in conjunction with the heterogeneity has been elusive. Here we investigate the redox-coupled folding dynamics of equine heart cytochrome c (cyt-c) induced by external electron injection by using time-resolved X-ray solution scattering. A systematic kinetic analysis unveils a kinetic model for its folding with a stretched exponential behavior during the transition toward the folded state. With the aid of the ensemble optimization method combined with molecular dynamics simulations, we found that during the folding the heterogeneously populated ensemble of the unfolded state is converted to a narrowly populated ensemble of folded conformations. These observations obtained from the kinetic and the structural analyses of X-ray scattering data reveal that the folding dynamics of cyt-c accompanies many parallel pathways associated with the heterogeneously populated ensemble of unfolded conformations, resulting in the stretched exponential kinetics at room temperature. This finding provides direct evidence with a view to microscopic protein conformations that the cyt-c folding initiates from a highly heterogeneous unfolded state, passes through still diverse intermediate structures, and reaches structural homogeneity by arriving at the folded state.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2020

Carrier-assisted One-pot Sample Preparation for Targeted Proteomics Analysis of Small Numbers of Human Cells

Protein analysis of small numbers of human cells is primarily achieved by targeted proteomics with antibody-based immunoassays, which have inherent limitations (e.g., low multiplex and unavailability of antibodies for new proteins). Mass spectrometry (MS)-based targeted proteomics has emerged as an alternative because it is antibody-free, high multiplex, and has high specificity and quantitation accuracy. Recent advances in MS instrumentation make MS-based targeted proteomics possible for multiplexed quantification of highly abundant proteins in single cells. However, there is a technical challenge for effective processing of single cells with minimal sample loss for MS analysis. To address this issue, we have recently developed a convenient protein carrier-assisted one-pot sample preparation coupled with liquid chromatography (LC) - selected reaction monitoring (SRM) termed cLC-SRM for targeted proteomics analysis of small numbers of human cells. This method capitalizes on using the combined excessive exogenous protein as a carrier and low-volume one-pot processing to greatly reduce surface adsorption losses as well as high-specificity LC-SRM to effectively address the increased dynamic concentration range due to the addition of exogeneous carrier protein. Its utility has been demonstrated by accurate quantification of most moderately abundant proteins in small numbers of cells (e.g., 10-100 cells) and highly abundant proteins in single cells. The easy-to-implement features and no need for specific devices make this method readily accessible to most proteomics laboratories. In this study, we have provided a detailed protocol for cLC-SRM analysis of small numbers of human cells including cell sorting, cell lysis and digestion, LC-SRM analysis, and data analysis. Further improvements in detection sensitivity and sample throughput are needed towards targeted single-cell proteomics analysis. We anticipate that cLC-SRM will be broadly applied to biomedical research and systems biology with the potential of facilitating precision medicine.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

The impact of physiologically relevant temperatures on physical properties of thylakoid membranes: a molecular dynamics study

Thylakoid membranes are energy-converting membranes with a unique lipid composition. Though the membranes are primarily composed of proteins, their photosynthetic function is strongly influenced by the lipid constituents. Here we characterize, with molecular dynamics (MD) simulations, lipid bilayers with compositions representative of plant thylakoid membranes. We determine, in a wide range of temperatures, the physical parameters of the model membranes which are relevant for the photosynthetic function. We found a marked impact of temperature on membrane permeability due to a combination of increased compressibility and curvature of the membrane at elevated temperatures. With increasing temperatures, we observed increasingly smeared transmembrane density profiles of the membrane forming lipid headgroups predicting increased membrane flexibility. The diffusion coefficient of the lipids increased with temperature without apparent specificity for lipid species. Instead of a comprehensive experimental dataset in the relevant temperature range, we quantitatively compared and validated our MD results with MD simulations on a dipalmitoylphosphatidylcholine model system.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS2007

Chromosome Model reveals Dynamic Redistribution of DNA Damage into Nuclear Sub-domains

Several proteins involved in the response to DNA double strand breaks (DSB) form microscopically visible nuclear domains, or foci, after exposure to ionizing radiation. Radiation-induced foci (RIF) are believed to be located where DNA damage is induced. To test this assumption, we analyzed the spatial distribution of 53BP1, phosphorylated ATM and gammaH2AX RIF in cells irradiated with high linear energy transfer (LET) radiation. Since energy is randomly deposited along high-LET particle paths, RIF along these paths should also be randomly distributed. The probability to induce DSB can be derived from DNA fragment data measured experimentally by pulsed-field gel electrophoresis. We used this probability in Monte Carlo simulations to predict DSB locations in synthetic nuclei geometrically described by a complete set of human chromosomes, taking into account microscope optics from real experiments. As expected, simulations produced DNA-weighted random (Poisson) distributions. In contrast, the distributions of RIF obtained as early as 5 min after exposure to high LET (1 GeV/amu Fe) were non-random. This deviation from the expected DNA-weighted random pattern can be further characterized by relative DNA image measurements. This novel imaging approach shows that RIF were located preferentially at the interface between high and low DNA density regions, and were more frequent in regions with lower density DNA than predicted. This deviation from random behavior was more pronounced within the first 5 min following irradiation for phosphorylated ATM RIF, while gammaH2AX and 53BP1 RIF showed very pronounced deviation up to 30 min after exposure. These data suggest the existence of repair centers in mammalian epithelial cells. These centers would be nuclear sub-domains where DNA lesions would be collected for more efficient repair.

Costes, Sylvain V.↗
DOE OSTI2023

Structure of the Sec14 domain of Kalirin reveals a distinct class of lipid-binding module in RhoGEFs

Gated entry of lipophilic ligands into the enclosed hydrophobic pocket in stand-alone Sec14 domain proteins often links lipid metabolism to membrane trafficking. Similar domains occur in multidomain mammalian proteins that activate small GTPases and regulate actin dynamics. The neuronal RhoGEF Kalirin, a central regulator of cytoskeletal dynamics, contains a Sec14 domain (Kal bSec14 ) followed by multiple spectrin-like repeats and catalytic domains. Previous studies demonstrated that Kalirin lacking its Sec14 domain fails to maintain cell morphology or dendritic spine length, yet whether and how Kal bSec14 interacts with lipids remain unknown. Here, we report the structural and biochemical characterization of Kal bSec14 . Kal bSec14 adopts a closed conformation, sealing off the canonical ligand entry site, and instead employs a surface groove to bind a limited set of lysophospholipids. The low-affinity interactions of Kal bSec14 with lysolipids are expected to serve as a general model for the regulation of Rho signaling by other Sec14-containing Rho activators.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Environmental Contributions to Proton Sharing in Protein Low-Barrier Hydrogen Bonds

Hydrogen bonds (H-bonds) are central to biomolecular structure and dynamics. Although H-bonds are typically characterized by well-defined proton positions, proton delocalization has been proposed to play a role in facilitating enzyme catalysis and allostery in some systems. Experimentally locating protons is difficult, hampering the study of proton mobility in H-bonds. We used neutron crystallography, atomic resolution X-ray bond length analysis, and large quantum mechanics/molecular mechanics-Born–Oppenheimer molecular dynamics (QM/MM-BOMD) simulations to comprehensively characterize the shared proton/deuteron in a Glu–Asp low-barrier hydrogen bond (LBHB) in the bacterial protein YajL that is a conventional H-bond in the homologous disease-associated human protein DJ-1. X-ray bond length analysis of protiated and perdeuterated DJ-1 and YajL shows no significant effect of deuteron substitution on these carboxylic acid-carboxylate H-bonds but does reveal an effect at the active site glutamic acid near a cysteine thiolate. Residues in an H-bonded network that might favor LBHB formation in YajL were interrogated by the mutation of homologous residues in DJ-1. A distal DJ-1 substitution increases proton delocalization in the Glu–Asp H-bond, demonstrating that mutations within extended H-bond networks can modulate proton transfer barriers in carboxylic acid-carboxylate H-bonds. In addition, proton mobility in the H-bond is correlated with dimer-spanning motions in the QM/MM-BOMD simulations of YajL and DJ-1. Our results show that proton delocalization can be tuned using combined bioinformatic, structural, and computational information, opening the possibility of using engineered proton delocalization as a probe of H-bonding environments and as a tool to test hypotheses about LBHB function.

Lin, Jiusheng [University of Nebraska, Lincoln, NE↗
DOE OSTI2024

Molecular basis of TMED9 oligomerization and entrapment of misfolded protein cargo in the early secretory pathway

Intracellular accumulation of misfolded proteins causes serious human proteinopathies. The transmembrane emp24 domain 9 (TMED9) cargo receptor promotes a general mechanism of cytotoxicity by entrapping misfolded protein cargos in the early secretory pathway. However, the molecular basis for this TMED9-mediated cargo retention remains elusive. Here, we report cryo–electron microscopy structures of TMED9, which reveal its unexpected self-oligomerization into octamers, dodecamers, and, by extension, even higher-order oligomers. The TMED9 oligomerization is driven by an intrinsic symmetry mismatch between the trimeric coiled coil domain and the tetrameric transmembrane domain. Using frameshifted Mucin 1 as an example of aggregated disease-related protein cargo, we implicate a mode of direct interaction with the TMED9 luminal Golgi-dynamics domain. The structures suggest and we confirm that TMED9 oligomerization favors the recruitment of coat protein I (COPI), but not COPII coatomers, facilitating retrograde transport and explaining the observed cargo entrapment. Our work thus reveals a molecular basis for TMED9-mediated misfolded protein retention in the early secretory pathway.

Science & Technology - Other Topics↗
DOE OSTI2025

Molecular Modeling and Molecular Dynamics Simulation of a Packed and Intact Bacterial Microcompartment

Bacterial microcompartments (BMCs) are protein-bound organelles found in some bacteria which encapsulate enzymes for enhanced catalytic activity. These compartments spatially sequester enzymes within semipermeable shell proteins and are packed full of enzyme cargoes and metabolites as they fulfill their function. Coupling together recent SAXS and proteomics work, it is possible to develop molecular models for these microcompartments and interrogate enzyme and metabolite dynamics within. Our primary goal of this study is to quantify the permeability of metabolite glyceraldehyde-3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP) across the BMC shell through classical molecular dynamics simulation. The Haliangium ochraceum model of BMC shell (PDB: 6MZX) was used to model an intact BMC of approximately 10 million atoms. Working at this scale presented its own challenges in managing large data sets, with multiple challenges and hardware advances discussed that facilitated this work. Over approximately 750 ns of aggregate simulation, we see multiple permeation events for these metabolites that were added at high concentration through the pores present within BMC shell tiles. When compared to independent permeability estimates for the same metabolites determined through replica exchange umbrella sampling simulations, the permeabilities varied by approximately 3 orders of magnitude. Regardless, the permeability coefficients for both G3P and DHAP are highly similar and very high, such that only very small concentration gradients can be maintained across the BMC shell between the cytosol and BMC interior. The large simulation systems also facilitated comparisons for molecular diffusivity in the crowded environment within the BMC shell. By our estimates, the viscosity within a packed BMC shell is at least 10-fold higher than it would be in neat solution and is the real driver for varying permeability estimates we obtained through simulation. These findings will be used as design inputs for future bioengineering efforts to make products from BMCs, highlighting how permeable BMC shells can be.

Diffusion↗
DOE OSTI2023

Bio-Based Phase Change Materials (PCMs) for Thermal Energy Storage (Final Scientific/Technical Report)

The goal of this project is to develop a novel bio-based phase change material (PCM) derived from squid ring teeth (SRT) proteins, and design a prototype heat exchanger based on these bio-based PCMs for energy storage and dynamic heat exchange for building thermal energy storage systems. The PCMs, derived from SRT proteins, will demonstrate room temperature energy storage capacities and switchable thermal conductivities that redefine the current state-of-the-art (SOA) for building thermal energy storage. Further, in a single material and with a single manufacturing processes, our proposed thermal battery will be developed with “on demand” thermal conductivity for rapid charging/discharging but superior insulation during energy storage periods. More specifically, our bio-based PCMs have demonstrated: 1) the potential for increased energy storage capacity (i.e., greater than paraffines at room temperature); 2) tunability in thermal conductivity with the largest thermal conductivity switching ratios for an intrinsic material reported to date, and 3) a 100% recyclable and biodegradable PCM with low volatility and toxicity and scalability in its manufacture for both residential and commercial applications. The already established ability for roll-to-roll processing of these non-toxic, non-flammable SRT composites along with their carbon-neutral manufacturing processes that has been pioneered by our team make this solution a disruptive and impactful technology to redefine the current SOA of energy storage technologies. The outcomes of this effort have been: 1) the identification of new bio-based PCM that establishes a new SOA for thermal conductivity and energy storage density at room temperature and 2) the development of a new experimental technique to measure the energy storage density via latent heat measurements during melting of thin films. This new technique can be applied to thin films (as thin as < 1 micrometer), and represents a novel approach for thin film energy storage density measurements. Dynamic thermal energy storage is the missing technology that will enable a grid- interactive efficient building (GEB). For a “smart” building capable of connecting with the power grid, the media must be inexpensive and possess thermal switching capabilities to control the time-dependent heat flow into (and out of) the PCM on demand. Unique to the material system in this program, programmable SRT-based PCM show improvements as compared to traditionally used PCMs, and thus its technical performance will represent a leap forward for the future GEB concept.

25 ENERGY STORAGE↗
DOE OSTI2023

Low-pass spectral analysis of time-resolved serial femtosecond crystallography data

Low-pass spectral analysis (LPSA) is a recently developed dynamics retrieval algorithm showing excellent retrieval properties when applied to model data affected by extreme incompleteness and stochastic weighting. In this work, we apply LPSA to an experimental time-resolved serial femtosecond crystallography (TR-SFX) dataset from the membrane protein bacteriorhodopsin (bR) and analyze its parametric sensitivity. While most dynamical modes are contaminated by nonphysical high-frequency features, we identify two dominant modes, which are little affected by spurious frequencies. The dynamics retrieved using these modes shows an isomerization signal compatible with previous findings. We employ synthetic data with increasing timing uncertainty, increasing incompleteness level, pixel-dependent incompleteness, and photon counting errors to investigate the root cause of the high-frequency contamination of our TR-SFX modes. By testing a range of methods, we show that timing errors comparable to the dynamical periods to be retrieved produce a smearing of dynamical features, hampering dynamics retrieval, but with no introduction of spurious components in the solution, when convergence criteria are met. Using model data, we are able to attribute the high-frequency contamination of low-order dynamical modes to the high levels of noise present in the data. Finally, we propose a method to handle missing observations that produces a substantial dynamics retrieval improvement from synthetic data with a significant static component. Reprocessing of the bR TR-SFX data using the improved method yields dynamical movies with strong isomerization signals compatible with previous findings.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2021

Development of Martini 2.2 parameters for N -glycans: a case study of the HIV-1 Env glycoprotein dynamics

N-linked glycans are ubiquitous in nature and play key roles in biology. For example, glycosylation of pathogenic proteins is a common immune evasive mechanism, hampering the development of successful vaccines. Due to their chemical variability and complex dynamics, an accurate molecular understanding of glycans is still limited by the lack of effective resolution of current experimental approaches. Here, we have developed and implemented a reductive model based on the popular Martini 2.2 coarse-grained force field for the computational study of N-glycosylation. We used the HIV-1 Env as a direct applied example of a highly glycosylated protein. Finally, our results indicate that the model not only reproduces many observables in very good agreement with a fully atomistic force field but also can be extended to study large amount of glycosylation variants, a fundamental property that can aid in the development of drugs and vaccines.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Ligand-Binding-Site Refinement to Generate Reliable Holo Protein Structure Conformations from Apo Structures

The first important step in a structure-based virtual screening is the judicious selection of a receptor protein. In cases where the holo protein receptor structure is unavailable, significant reduction in virtual screening performance has been reported. In this work, we present a robust method to generate reliable holo protein structure conformations from apo structures using molecular dynamics (MD) simulation with restraints derived from holo structure binding-site templates. We perform benchmark tests on two different datasets: 40 structures from a directory of useful decoy-enhanced (DUD-E) and 84 structures from the Gunasekaran dataset. Our results show successful refinement of apo binding-site structures toward holo conformations in 82% of the test cases. In addition, virtual screening performance of 40 DUD-E structures is significantly improved using our MD-refined structures as receptors with an average enrichment factor (EF), an EF1% value of 6.2 compared to apo structures with 3.5. Docking of native ligands to the refined structures shows an average ligand root mean square deviation (RMSD) of 1.97 Å (DUD-E dataset and Gunasekaran dataset) relative to ligands in the holo crystal structures, which is comparable to the self-docking (i.e., docking of the native ligand back to its crystal structure receptor) average, 1.34 Å (DUD-E dataset) and 1.36 Å (Gunasekaran dataset). On the other hand, docking to the apo structures yields an average ligand RMSD of 3.65 Å (DUD-E) and 2.90 Å (Gunasekaran). These results indicate that our method is robust and can be useful to improve virtual screening performance of apo structures.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Water, Solute, and Ion Transport in De Novo-Designed Membrane Protein Channels

Biological organisms engineer peptide sequences to fold into membrane pore proteins capable of performing a wide variety of transport functions. Synthetic de novo-designed membrane pores can mimic this approach to achieve a potentially even larger set of functions. Here, in this work, we explore water, solute, and ion transport in three de novo designed β-barrel membrane channels in the 5–10 Å pore size range. We show that these proteins form passive membrane pores with high water transport efficiencies and size rejection characteristics consistent with the pore size encoded in the protein structure. Ion conductance and ion selectivity measurements also show trends consistent with the pore size, with the two larger pores showing weak cation selectivity. MD simulations of water and ion transport and solute size exclusion are consistent with the experimental trends and provide further insights into structure–function correlations in these membrane pores.

59 BASIC BIOLOGICAL SCIENCES↗