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DOE OSTI2023

Structural basis of impaired disaggregase function in the oxidation-sensitive SKD3 mutant causing 3-methylglutaconic aciduria

Abstract Mitochondria are critical to cellular and organismal health. To prevent damage, mitochondria have evolved protein quality control machines to survey and maintain the mitochondrial proteome. SKD3, also known as CLPB, is a ring-forming, ATP-fueled protein disaggregase essential for preserving mitochondrial integrity and structure. SKD3 deficiency causes 3-methylglutaconic aciduria type VII (MGCA7) and early death in infants, while mutations in the ATPase domain impair protein disaggregation with the observed loss-of-function correlating with disease severity. How mutations in the non-catalytic N-domain cause disease is unknown. Here, we show that the disease-associated N-domain mutation, Y272C, forms an intramolecular disulfide bond with Cys267 and severely impairs SKD3 Y272C function under oxidizing conditions and in living cells. While Cys267 and Tyr272 are found in all SKD3 isoforms, isoform-1 features an additional α-helix that may compete with substrate-binding as suggested by crystal structure analyses and in silico modeling, underscoring the importance of the N-domain to SKD3 function.

59 BASIC BIOLOGICAL SCIENCES↗

NASA NTRS2005

Rotating Vessels for Growing Protein Crystals

Rotating vessels have been proposed as means of growing larger, more nearly uniform protein crystals than would otherwise be possible in the presence of normal Earth gravitation. Heretofore, nonrotating vessels have been used. It is difficult to grow high-quality protein crystals in the terrestrial gravitational field because of convection plumes created by the interaction between gravitation and density gradients in protein-solution depletion layers around growing crystals. The density gradients and the associated convection plumes cause the surfaces of growing crystals to be exposed to nonuniform solution densities, thereby causing the crystals to form in irregular shapes. The microgravitational environment of outer space has been utilized to eliminate gravitation-induced convection, but this approach is generally not favorable because of the high cost and limited availability of space flight. The use of a rotating vessel according to the proposal is intended to ameliorate the effects of gravitation and the resultant convection, relative to the corresponding effects in a non-rotating vessel. The rotation would exert an averaging effect over time, distributing the convective force on the depletion layer. Therefore, the depletion layer would be more nearly uniform and, as a result, the growing crystal would be more nearly perfect. The proposal admits of variations (see figure), including the following: The growing crystal could be rotated about its own central axis or an external axis. The crystal-growth vessel could be of any of various shapes, including cylindrical, hemispherical, conical, and combinations thereof. The crystal-growth vessel could be suspended in a viscous fluid in an outer vessel to isolate the growing crystal from both ambient vibrations and vibrations induced by a mechanism that drives the rotation. The rotation could be coupled to the crystal-growth vessel by viscous or magnetic means. The crystal-growth vessel could be supported within the outer vessel by use of a magnetic field. The crystal-growth vessel and the outer vessel could be configured in a variety of ways to facilitate heat transfer, instrumentation, and rotation.

Cottingham, Paul↗

DOE OSTI2021

Quality control of mislocalized and orphan proteins

A healthy and functional proteome is essential to cell physiology. However, this is constantly being challenged as most steps of protein metabolism are error-prone and changes in the physico-chemical environment can affect protein structure and function, thereby disrupting proteome homeostasis. Among a variety of potential mistakes, proteins can be targeted to incorrect compartments or subunits of protein complexes may fail to assemble properly with their partners, resulting in the formation of mislocalized and orphan proteins, respectively. Quality control systems are in place to handle these aberrant proteins, and to minimize their detrimental impact on cellular functions. Here, we discuss recent findings on quality control mechanisms handling mislocalized and orphan proteins. We highlight common principles involved in their recognition and summarize how accumulation of these aberrant molecules is associated with aging and disease.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2024

In situ counter-diffusion crystallization and long-term crystal preservation in microfluidic fixed targets for serial crystallography

Compared with batch and vapor diffusion methods, counter diffusion can generate larger and higher-quality protein crystals yielding improved diffraction data and higher-resolution structures. Typically, counter-diffusion experiments are conducted in elongated chambers, such as glass capillaries, and the crystals are either directly measured in the capillary or extracted and mounted at the X-ray beamline. Despite the advantages of counter-diffusion protein crystallization, there are few fixed-target devices that utilize counter diffusion for crystallization. In this article, different designs of user-friendly counter-diffusion chambers are presented which can be used to grow large protein crystals in a 2D polymer microfluidic fixed-target chip. Methods for rapid chip fabrication using commercially available thin-film materials such as Mylar, propylene and Kapton are also detailed. Rules of thumb are provided to tune the nucleation and crystal growth to meet users' needs while minimizing sample consumption. These designs provide a reliable approach to forming large crystals and maintaining their hydration for weeks and even months. This allows ample time to grow, select and preserve the best crystal batches before X-ray beam time. Importantly, the fixed-target microfluidic chip has a low background scatter and can be directly used at beamlines without any crystal handling, enabling crystal quality to be preserved. The approach is demonstrated with serial diffraction of photoactive yellow protein, yielding 1.32 Å resolution at room temperature. Fabrication of this standard microfluidic chip with commercially available thin films greatly simplifies fabrication and provides enhanced stability under vacuum. These advances will further broaden microfluidic fixed-target utilization by crystallographers.

Liu, Zhongrui↗

DOE OSTI2022

A polypeptide model for toxic aberrant proteins induced by aminoglycoside antibiotics

Aminoglycoside antibiotics interfere with the selection of cognate tRNAs during translation, resulting in the synthesis of aberrant proteins that are the ultimate cause of cell death. However, the toxic potential of aberrant proteins and how they avoid degradation by the cell’s protein quality control (QC) machinery are not understood. Here we report that levels of the heat shock (HS) transcription factor σ32 increased sharply following exposure of Escherichia coli to the aminoglycoside kanamycin (Kan), suggesting that at least some of the aberrant proteins synthesized in these cells were recognized as substrates by DnaK, a molecular chaperone that regulates the HS response, the major protein QC pathway in bacteria. To further investigate aberrant protein toxic potential and interaction with cell QC factors, we studied an acutely toxic 48-residue polypeptide (ARF48) that is encoded by an alternate reading frame in a plant cDNA. As occurred in cells exposed to Kan, σ32 levels were strongly elevated following ARF48 expression, suggesting that ARF48 was recognized as a substrate by DnaK. Paradoxically, an internal 10-residue region that was tightly bound by DnaK in vitro also was required for the ARF48 toxic effect. Despite the increased levels of σ32, levels of several HS proteins were unchanged following ARF48 expression, suggesting that the HS response had been aborted. Nucleoids were condensed and cell permeability increased rapidly following ARF48 expression, together suggesting that ARF48 disrupts DNA-membrane interactions that could be required for efficient gene expression. Our results are consistent with earlier studies showing that aberrant proteins induced by aminoglycoside antibiotics disrupt cell membrane integrity. Insights into the mechanism for this effect could be gained by further study of the ARF48 model system.

36 MATERIALS SCIENCE↗

DOE OSTI2022

Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase

Translation is a tightly regulated process that ensures optimal protein quality and enables adaptation to energy/nutrient availability. The α-kinase eukaryotic elongation factor 2 kinase (eEF-2K), a key regulator of translation, specifically phosphorylates the guanosine triphosphatase eEF-2, thereby reducing its affinity for the ribosome and suppressing the elongation phase of protein synthesis. eEF-2K activation requires calmodulin binding and autophosphorylation at the primary stimulatory site, T348. Biochemical studies predict a calmodulin-mediated activation mechanism for eEF-2K distinct from other calmodulin-dependent kinases. Here, we resolve the atomic details of this mechanism through a 2.3-Å crystal structure of the heterodimeric complex of calmodulin and the functional core of eEF-2K (eEF-2K TR ). This structure, which represents the activated T348-phosphorylated state of eEF-2K TR , highlights an intimate association of the kinase with the calmodulin C-lobe, creating an “activation spine” that connects its amino-terminal calmodulin-targeting motif to its active site through a conserved regulatory element.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

NASA NTRS1993

Recent results and new hardware developments for protein crystal growth in microactivity

Protein crystal growth experiments have been performed on 16 space shuttle missions since April, 1985. The initial experiments utilized vapor diffusion crystallization techniques similar to those used in laboratories for earth-based experiments. More recent experiments have utilized temperature induced crystallization as an alternative method for growing high quality protein crystals in microgravity. Results from both vapor diffusion and temperature induced crystallization experiments indicate that proteins grown in microgravity may be larger, display more uniform morphologies, and yield diffraction data to significantly higher resolutions than the best crystals of these proteins grown on earth.

Delucas, L. J.↗

DOE OSTI2021

Neurons die with heightened but functional macro- and chaperone mediated autophagy upon increased amyloid-ß induced toxicity with region-specific protection in prolonged intermittent fasting

Highlights: • Macroautophagy (MA) is strongly engaged upon APP overexpression and remains high over time. • APP colocalization with macroautophagy components remains increased until late, promoting continuous recruitment to the autophagy machinery. • Robust chaperone-mediated autophagy (CMA) engagement is observed in late APP overexpression. • Macroautophagic flux during APP overexpression is preserved, even at late time points, suggesting functional autophagy in the face of apoptosis onset. • Macroautophagy impairment increases markers of amyloidogenesis and further exacerbates the onset of apoptotic cell death. Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant socio-economic impact that is exacerbated by the rapid increase in population aging, particularly impacting already burdened health care systems of poorly resourced countries. Accumulation of the amyloid-β (Aβ) peptide, generated through amyloid precursor protein (APP) processing, manifesting in senile plaques, is a well-established neuropathological feature. Aβ plays a key role in driving synaptic dysfunction, neuronal cell loss, glial cell activation and oxidative stress associated with the pathogenesis of AD. Thus, the enhanced clearance of Aβ peptide though modulation of the mechanisms that regulate intracellular Aβ metabolism and clearance during AD progression have received major attention. Autophagy, a lysosome-based major proteolytic pathway, plays a crucial role in intracellular protein quality control and has been shown to contribute to the clearance of Aβ peptide. However, to what extent autophagy activity remains upregulated and functional in the process of increasing Aβ neurotoxicity is largely unclear. Here, we investigated the extent of neuronal toxicity in vitro by characterising autophagic flux, the expression profile of key amyloidogenic proteins, and proteins associated with prominent subtypes of the autophagy pathway to dissect the interplay between the engagement of proteolytic pathways and cell death onset in the context of APP overexpression. Moreover, we assessed the neuroprotective effects of a caloric restriction regime in vivo on the modulation of autophagy in specific brain regions. Our results reveal that autophagy is upregulated in the presence of high levels of APP and Aβ and remains heightened and functional despite concomitant apoptosis induction, suggestive of a mismatch between autophagy cargo generation and clearance capacity. These findings were confirmed when implementing a prolonged intermittent fasting (IF) intervention in a model of paraquat-induced neuronal toxicity, where markers of autophagic activity were increased, while apoptosis onset and lipid peroxidation were robustly decreased in brain regions associated with neurodegeneration. This work highlights that especially caloric restriction mimetics and controlled prolonged IF may indeed be a highly promising therapeutic strategy at all stages of AD-associated pathology progression, for a cell-inherent and cell specific augmentation of Aβ clearance through the powerful engagement of autophagy and thereby robustly contributing to neuronal protection.

60 APPLIED LIFE SCIENCES↗

NASA NTRS2000

Acetylated Lysozyme as Impurity in Lysozyme Crystals: Constant Distribution Coefficient

Hen egg white lysozyme (HEWL) was acetylated to modify molecular charge keeping the molecular size and weight nearly constant. Two derivatives, A and B, more and less acetylated, respectively, were obtained, separated, purified and added to the solution from which crystals of tetragonal HEWL crystals were grown. Amounts of the A or B impurities added were 0.76, 0.38 and 0.1 milligram per millimeter while HEWL concentration were 20, 30 and 40 milligram per milliliter. The crystals grown in 18 experiments for each impurity were dissolved and quantities of A or B additives in these crystals were analyzed by cation exchange high performance liquid chromatography. All the data for each set of 18 samples with the different impurity and regular HEWL concentrations is well described by one distribution coefficient K = 2.15 plus or minus 0.13 for A and K = 3.42 plus or minus 0.25 for B. The observed independence of the distribution coefficient on both the impurity concentration and supersaturation is explained by the dilution model described in this paper. It shows that impurity adsorption and incorporation rate is proportional to the impurity concentration and that the growth rate is proportional to the crystallizing protein in solution. With the kinetic coefficient for crystallization, beta = 5.10(exp -7) centimeters per second, the frequency at which an impurity molecule near the growing interface irreversibly joins a molecular site on the crystal was found to be 3 1 per second, much higher than the average frequency for crystal molecules. For best quality protein crystals it is better to have low microheterogeneous protein impurity concentration and high supers aturation.

Thomas, B. R.↗

DOE OSTI2022

Effects of soybean 7S protein on the quality and digestibility of dry rice noodles under twin‐screw extrusion process

Summary Starch and protein are important components of food, the mixed system formed between them (complexes, gels, mixtures, etc.) can improve the physical and chemical properties of starch and protein, and its potential application in the food industry has also attracted widespread attention. In this study, indica rice flour and soybean 7S protein (β‐Conglycinin) were used as the experimental materials to explore the effect of soybean 7S protein addition on the quality and digestibility of rice noodles. Aims to develop rice noodles with high protein and low GI, so that people can take care of their health while satisfying their appetites. The results showed that with the increase of soybean 7S protein addition, the starch digestibility decreased, resulting in the estimated glycaemic index (eGI) and glycaemic load (GL) decreasing. However, the cooking loss rate and breakage rate of rice noodles gradually increased, the water absorption first increased and then decreased, and the taste of rice noodles is acceptable when the 7S protein addition amount is within 9%. The interaction between starch and soybean 7S protein was mediated by weak interactions such as hydrogen bonds and hydrophobic forces indicated by Fourier transform infrared spectroscopy (FTIR) and X‐ray diffraction (XRD).

Qiao, Fan↗

DOE OSTI2023

Enzymes in 3D: Synthesis, remodelling, and hydrolysis of cell wall (1,3;1,4)-β-glucans

Abstract Recent breakthroughs in structural biology have provided valuable new insights into enzymes involved in plant cell wall metabolism. More specifically, the molecular mechanism of synthesis of (1,3;1,4)-β-glucans, which are widespread in cell walls of commercially important cereals and grasses, has been the topic of debate and intense research activity for decades. However, an inability to purify these integral membrane enzymes or apply transgenic approaches without interpretative problems associated with pleiotropic effects has presented barriers to attempts to define their synthetic mechanisms. Following the demonstration that some members of the CslF sub-family of GT2 family enzymes mediate (1,3;1,4)-β-glucan synthesis, the expression of the corresponding genes in a heterologous system that is free of background complications has now been achieved. Biochemical analyses of the (1,3;1,4)-β-glucan synthesized in vitro, combined with 3-dimensional (3D) cryogenic-electron microscopy and AlphaFold protein structure predictions, have demonstrated how a single CslF6 enzyme, without exogenous primers, can incorporate both (1,3)- and (1,4)-β-linkages into the nascent polysaccharide chain. Similarly, 3D structures of xyloglucan endo-transglycosylases and (1,3;1,4)-β-glucan endo- and exohydrolases have allowed the mechanisms of (1,3;1,4)-β-glucan modification and degradation to be defined. X-ray crystallography and multi-scale modeling of a broad specificity GH3 β-glucan exohydrolase recently revealed a previously unknown and remarkable molecular mechanism with reactant trajectories through which a polysaccharide exohydrolase can act with a processive action pattern. The availability of high-quality protein 3D structural predictions should prove invaluable for defining structures, dynamics, and functions of other enzymes involved in plant cell wall metabolism in the immediate future.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Energy-Screened Many-Body Expansion for Protein–Ligand Interactions: Examining Convergence for Metalloenzymes Through Seven–Body Interactions

Fragment-based quantum chemistry is a powerful strategy for calculating protein−ligand interaction energies using quantum chemistry methods. Rigorous convergence often requires hundreds of atoms in the protein binding-site model, especially if that model is constructed using distance-based criteria to select amino acid residues, while three- and four-body calculations exhibit instability related to combinatorial proliferation in the number of subsystem calculations. Here, we report an energy-based screening protocol for the many-body expansion applied to protein−ligand interactions, implemented in the open-source FRAGME∩T code. Using a combination of aggressive screening based on semiempirical quantum chemistry, with an improved graph-theoretical algorithm to eliminate unimportant subsystems, we are able to perform n-body calculations up to n = 7 using density functional theory in triple-ζ basis sets. Distance cutoffs further reduce the cost without compromising accuracy. Rapid and stable convergence of the many-body expansion is obtained by n = 4, for a pair of metalloenzymes in which a divalent ion coordinates directly to the ligand. As compared to previous results that relied solely on distance cutoffs, oscillations in the n-body corrections are reduced or eliminated, although residual errors remain in one case. This work demonstrates that benchmark-quality protein−ligand interaction energies can be systematically converged using a method with excellent parallel efficiency and scalability.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

DOE OSTI2021

Isoform-specific functions of synaptopodin-2 variants in cytoskeleton stabilization and autophagy regulation in muscle under mechanical stress

Highlights: • Muscle cells express different synaptopodin-2 isoforms with individual functions. • Reduced SYNPO2 expression results in enhanced vulnerability of myofibrils. • SYNPO2e recruites BAG3 to mechanically stressed myofibrillar areas. • SYNPO2 is an organizer and regulator of BAG3-containing proteostasis systems. • BAG3 forms functionally distinct protein complexes with different SYNPO2 isoforms. Protein homeostasis (proteostasis) in multicellular organisms depends on the maintenance of force-bearing and force-generating cellular structures. Within myofibrillar Z-discs of striated muscle, isoforms of synaptopodin-2 (SYNPO2/myopodin) act as adapter proteins that are engaged in proteostasis of the actin-crosslinking protein filamin C (FLNc) under mechanical stress. SYNPO2 directly binds F-actin, FLNc and α-actinin and thus contributes to the architectural features of the actin cytoskeleton. By its association with autophagy mediating proteins, i.e. BAG3 and VPS18, SYNPO2 is also engaged in protein quality control and helps to target mechanical unfolded and damaged FLNc for degradation. Here we show that deficiency of all SYNPO2-isoforms in myotubes leads to decreased myofibrillar stability and deregulated autophagy under mechanical stress. In addition, isoform-specific proteostasis functions were revealed. The PDZ-domain containing variant SYNPO2b and the shorter, PDZ-less isoform SYNPO2e both localize to Z-discs. Yet, SYNPO2e is less stably associated with the Z-disc than SYNPO2b, and is dynamically transferred into FLNc-containing myofibrillar lesions under mechanical stress. SYNPO2e also recruits BAG3 into these lesions via interaction with the WW domain of BAG3. Our data provide evidence for a role of myofibrillar lesions as a transient quality control compartment essential to prevent and repair contraction-induced myofibril damage in muscle and indicate an important coordinating activity for SYNPO2 therein.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Cryo-EM structure of transmembrane AAA+ protease FtsH in the ADP state

Abstract AAA+ proteases regulate numerous physiological and cellular processes through tightly regulated proteolytic cleavage of protein substrates driven by ATP hydrolysis. FtsH is the only known family of membrane-anchored AAA+ proteases essential for membrane protein quality control. Although a spiral staircase rotation mechanism for substrate translocation across the FtsH pore has been proposed, the detailed conformational changes among various states have not been clear due to absence of FtsH structures in these states. We report here the cryo-EM structure for Thermotoga maritima FtsH ( Tm FtsH) in a fully ADP-bound symmetric state. Comparisons of the ADP-state structure with its apo-state and a substrate-engaged yeast YME1 structure show conformational changes in the ATPase domains, rather than the protease domains. A reconstruction of the full-length Tm FtsH provides structural insights for the dynamic transmembrane and the periplasmic domains. Our structural analyses expand the understanding of conformational switches between different nucleotide states in ATP hydrolysis by FtsH.

59 BASIC BIOLOGICAL SCIENCES↗

DOE OSTI2026

Assembly and Repair of the Photosystem II Reaction Center

This project investigated the biochemical and biophysical mechanisms governing assembly and repair of Photosystem II (PSII), the membrane protein complex responsible for solar-driven water oxidation in oxygenic photosynthesis. The work focused on three integrated areas: (1) protein–protein interactions that facilitate PSII assembly in cyanobacterial biogenesis centers, (2) the chemical mechanism of photo-assembly of the Mn 4 CaO 5 oxygen-evolving complex (OEC), and (3) mechanisms that target PSII reaction centers for degradation and repair in photosynthetic organisms. Using electron paramagnetic resonance spectroscopy, protein biochemistry, molecular genetics, quantitative mass spectrometry, and computational modeling, the project demonstrated that proton release events limit early steps of OEC assembly and that chloride and calcium ions facilitate Mn oxidation and intermediate stabilization. Complementary studies identified chaperone recruitment mechanisms in cyanobacterial PSII biogenesis centers and translation and protease factors involved in PSII turnover in Chlamydomonas. Together, these results establish proton management and coordinated protein quality control as central design principles in PSII assembly and repair and provide mechanistic insight relevant to biological and artificial photosynthetic systems.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

NASA NTRS1987

Food production and gas exchange system using blue-green alga (spirulina) for CELSS

In order to reduce the cultivation area required for the growth of higher plants in space adoption of algae, which have a higher photosynthetic ability, seems very suitable for obtaining oxygen and food as a useful source of high quality protein. The preliminary cultivation experiment for determining optimum cultivation conditions and for obtaining the critical design parameters of the cultivator itself was conducted. Spirulina was cultivated in the 6 liter medium containing a sodium hydrogen carbonate solution and a cultivation temperature controlled using a thermostat. Generated oxygen gas was separated using a polypropyrene porous hollow fiber membrane module. Through this experiment, oxygen gas (at a concentration of more than 46 percent) at a rate of 100 to approx. 150 ml per minute could be obtained.

Oguchi, Mitsuo↗

NASA NTRS2015

Space Biophysics: Accomplishments, Trends, Challenges

Physics and biology are inextricably linked. All the chemical and biological processes of life are dutifully bound to follow the rules and laws of physics. In space, these physical laws seem to turn on their head and biological systems, from microbes to humans, adapt and evolve in myriad ways to cope with the changed physical influences of the space environment. Gravity is the most prominent change in space that influences biology. In microgravity, the physical processes of sedimentation, density-driven convective flow, influence of surface tension and fluid pressure profoundly influence biology at the molecular and cellular level as well as at the whole-body level. Gravity sensing mechanisms are altered, structural and functional components of biology (such as bone and muscle) are reduced and changes in the way fluids and gasses behave also drive the way microbial systems and biofilms grow as well as the way plants and animals adapt. The radiation environment also effects life in space. Solar particle events and high energy cosmic radiation can cause serious damage to DNA and other biomolecules. The results can cause mutation, cellular damage or death, leading to health consequences of acute radiation damage or long-term health consequences such as increased cancer risk. Space Biophysics is the study and utilization of physical changes in space that cause changes in biological systems. The unique physical environment in space has been used successfully to grow high-quality protein crystals and 3D tissue cultures that could not be grown in the presence of unidirectional gravitational acceleration here on Earth. All biological processes that change in space have their root in a biophysical alteration due to microgravity and/or the radiation environment of space. In order to fully-understand the risks to human health in space and to fully-understand how humans, plants, animals and microbes can safely and effectively travel and eventually live for long periods beyond the protective environment of Earth, the biophysical properties underlying these changes must be studied, characterized and understood. This lecture reviews the current state of NASA biophysics research accomplishments and identifies future trends and challenges for biophysics research on the International Space Station and beyond.

Space Biophysics: Accomplishments↗

DOE OSTI2022

DISTEMA: distance map-based estimation of single protein model accuracy with attentive 2D convolutional neural network

Abstract Background Estimation of the accuracy (quality) of protein structural models is important for both prediction and use of protein structural models. Deep learning methods have been used to integrate protein structure features to predict the quality of protein models. Inter-residue distances are key information for predicting protein’s tertiary structures and therefore have good potentials to predict the quality of protein structural models. However, few methods have been developed to fully take advantage of predicted inter-residue distance maps to estimate the accuracy of a single protein structural model. Result We developed an attentive 2D convolutional neural network (CNN) with channel-wise attention to take only a raw difference map between the inter-residue distance map calculated from a single protein model and the distance map predicted from the protein sequence as input to predict the quality of the model. The network comprises multiple convolutional layers, batch normalization layers, dense layers, and Squeeze-and-Excitation blocks with attention to automatically extract features relevant to protein model quality from the raw input without using any expert-curated features. We evaluated DISTEMA’s capability of selecting the best models for CASP13 targets in terms of ranking loss of GDT-TS score. The ranking loss of DISTEMA is 0.079, lower than several state-of-the-art single-model quality assessment methods. Conclusion This work demonstrates that using raw inter-residue distance information with deep learning can predict the quality of protein structural models reasonably well. DISTEMA is freely at https://github.com/jianlin-cheng/DISTEMA

59 BASIC BIOLOGICAL SCIENCES↗