Secondary structure drives self-assembly in weakly segregated globular protein-rod block copolymers
Explore the source record for details and available documents.
99 GENERAL AND MISCELLANEOUS↗
SEARCH · Search NASA
Results for “secondary structure”
Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Generative design of de novo proteins based on secondary-structure constraints using an attention-based diffusion model
We report two generative deep-learning models that predict amino acid sequences and 3D protein structures on the basis of secondary-structure design objectives via either the overall content or the per-residue structure. Both models are robust regarding imperfect inputs and offer de novo design capacity because they can discover new protein sequences not yet discovered from natural mechanisms or systems. The residue-level secondary-structure design model generally yields higher accuracy and more diverse sequences. These findings suggest unexplored opportunities for protein designs and functional outcomes within the vast amino acid sequences beyond known proteins. Our models, based on an attention-based diffusion model and trained on a dataset extracted from experimentally known 3D protein structures, offer numerous downstream applications in the conditional generative design of various biological or engineering systems. Future work could include additional conditioning and an exploration of other functional properties of the generated proteins for various properties beyond structural objectives.
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
Sequence-Controlled Secondary Structures and Stimuli Responsiveness of Bioinspired Polyampholytes
In this work, a comprehensive study focusing on the influence of the sequence charge pattern on the secondary structure preferences of annealed polyampholytes and their responsiveness to external stimuli is presented. Two sequences are designed composed entirely of ionizable amino acids (charge fraction f=1), and an equal number of positive and negative charges (f + =f - =0.5) with distinct charge-patterns consisting of lysine and glutamic acid monomers. The study reveals that the sequence charge pattern has a significant influence on the secondary structure preferences of polyampholytes at physiological pH. Furthermore, it shows that external stimuli such as pH, ionic strength and solvent dielectric constant can be used to modulate the secondary structure of the two designed sequences. The observed secondary structure transformations for the two sequences are also substantially different from those determined for uniformly charged polypeptides-homo-polypeptides under matching conditions.
59 BASIC BIOLOGICAL SCIENCES↗
Skeletides: A Modular, Simplified Physical Model of Protein Secondary Structure
Three-dimensional (3D) models are essential for visualization and conceptual understanding of complex architectures such as protein structure. Although there is a plethora of software platforms that allow digital depictions of protein structure at an atomic level in silico, physical models are needed to convey an intuitive understanding of biomolecular architecture. However, it is a challenge to represent all the relevant features of proteins in a single physical model due to their sheer structural complexity. Here, we describe a modular protein model that focuses only on representation of the secondary structure—the underlying structural skeleton. The simplified model consists of amino acid units, which can be linked together to reproduce the two most fundamental structural features of protein secondary structure: the relative positions of the amino acid alpha carbon atoms, and the intra-main chain hydrogen bonding pattern. We use 3D printing and magnets to create a set of three modular amino acid building blocks, which when linked together into a chain, can faithfully represent alpha helices, beta sheets, and turns. These simple to make models can be used to quickly assemble the alpha carbon trace of an entire protein domain, which conveys a tactile experience of the complexity of protein skeletal architecture. These models highlight the modularity of protein structure: where a single structural unit, the amino acid, can be linked together to form a larger, regular secondary structure. These models also have a propensity to spontaneously organize into alpha helices and beta sheets, as demonstrated by their ability to autonomously assemble when placed in a circulating water tank. These models provide a missing educational tool to expand knowledge of protein structure, foster deeper insight into protein folding, and inspire greater interest in biomacromolecular architecture.
36 MATERIALS SCIENCE↗
Using a Coarse-Grained Modeling Framework to Identify Oligomeric Motifs with Tunable Secondary Structure
Coarse-grained modeling can be used to explore general theories that are independent of specific chemical detail. In this paper, we present cg_openmm, a Python-based simulation framework for modeling coarse-grained hetero-oligomers and screening them for structural and thermodynamic characteristics of cooperative secondary structures. cg_openmm facilitates the building of coarse-grained topology and random starting configurations, setup of GPU-accelerated replica exchange molecular dynamics simulations with the OpenMM software package, and features a suite of postprocessing thermodynamic and structural analysis tools. In particular, native contact analysis, heat capacity calculations, and free energy of folding calculations are used to identify and characterize cooperative folding transitions and stable secondary structures. In this work, we demonstrate the capabilities of cg_openmm on a simple 1–1 Lennard-Jones coarse-grained model, in which each residue contains 1 backbone and 1 side-chain bead. By scanning both nonbonded and bonded force-field parameter spaces at the coarse-grained level, we identify and characterize sets of parameters which result in the formation of stable helices through cooperative folding transitions. Furthermore, we show that the geometries and stabilities of these helices can be tuned by manipulating the force-field parameters.
36 MATERIALS SCIENCE↗
Transient local secondary structure in the intrinsically disordered C‐term of the Albino3 insertase
Albino3 (Alb3) is an integral membrane protein fundamental to the targeting and insertion of light‐harvesting complex (LHC) proteins into the thylakoid membrane. Alb3 contains a stroma‐exposed C‐terminus (Alb3‐Cterm) that is responsible for binding the LHC‐loaded transit complex before LHC membrane insertion. Alb3‐Cterm has been reported to be intrinsically disordered, but precise mechanistic details underlying how it recognizes and binds to the transit complex are lacking, and the functional roles of its four different motifs have been debated. Using a novel combination of experimental and computational techniques such as single‐molecule fluorescence resonance energy transfer, circular dichroism with deconvolution analysis, site‐directed mutagenesis, trypsin digestion assays, and all‐atom molecular dynamics simulations in conjunction with enhanced sampling techniques, we show that Alb3‐Cterm contains transient secondary structure in motifs I and II. The excellent agreement between the experimental and computational data provides a quantitatively consistent picture and allows us to identify a heterogeneous structural ensemble that highlights the local and transient nature of the secondary structure. This structural ensemble was used to predict both the inter‐residue distance distributions of single molecules and the apparent unfolding free energy of the transient secondary structure, which were both in excellent agreement with those determined experimentally. We hypothesize that this transient local secondary structure may play an important role in the recognition of Alb3‐Cterm for the LHC‐loaded transit complex, and these results should provide a framework to better understand protein targeting by the Alb3‐Oxa1‐YidC family of insertases.
Okoto, Patience S.↗
Secondary structures and mechanisms - Design trouble area for the space shuttle
The design of secondary structures and mechanisms for a reusable space shuttle can produce problems as serious as those involved in designing the primary structure and thermal protection system. Several events involving failure of secondary structures during the X-15 flight program have been selected to illustrate potential problem areas. Similar problems may be expected on future reusable vehicles until additional research provides adequate design information in these areas.
Eldon E. Kordes↗
Standardized Residue Numbering and Secondary Structure Nomenclature in the Class D β-Lactamases
Over 1370 class D β-lactamases are currently known, and they pose a serious threat to the effective treatment of many infectious diseases, particularly in some pathogenic bacteria where evolving carbapenemase activity has been reported. Detailed understanding of their molecular biology, enzymology, and structural biology are critically important, but the lack of a standardized residue numbering scheme and inconsistent secondary structure annotation has made comparative analyses sometimes difficult and cumbersome. Compounding this, in the post-AlphaFold world where we currently find ourselves, an extraordinary wealth of detailed structural information on these enzymes is literally at our fingertips; therefore it is vitally important that a standard numbering system is in place to facilitate the accurate and straightforward analysis of their structures. In conclusion, here we present a residue numbering and secondary structure scheme for the class D enzymes based on the sequence and structure of OXA-48 and apply it to test targets to demonstrate the ease with which it can be used.
59 BASIC BIOLOGICAL SCIENCES↗
A Novel Non‐Destructive Rapid Tool for Estimating Amino Acid Composition and Secondary Structures of Proteins in Solution
Abstract Amino‐acid protein composition plays an important role in biology, medicine, and nutrition. Here, a groundbreaking protein analysis technique that quickly estimates amino acid composition and secondary structure across various protein sizes, while maintaining their natural states is introduced and validated. This method combines multivariate statistics and the thermostable Raman interaction profiling (TRIP) technique, eliminating the need for complex preparations. In order to validate the approach, the Raman spectra are constructed of seven proteins of varying sizes by utilizing their amino acid frequencies and the Raman spectra of individual amino acids. These constructed spectra exhibit a close resemblance to the actual measured Raman spectra. Specific vibrational modes tied to free amino and carboxyl termini of the amino acids disappear as signals linked to secondary structures emerged under TRIP conditions. Furthermore, the technique is used inversely to successfully estimate amino acid compositions and secondary structures of unknown proteins across a range of sizes, achieving impressive accuracy ranging between 1.47% and 5.77% of root mean square errors (RMSE). These results extend the uses for TRIP beyond interaction profiling, to probe amino acid composition and structure.
Chemistry↗
Secondary structure determines electron transport in peptides
Proteins play a key role in biological electron transport, but the structure–function relationships governing the electronic properties of peptides are not fully understood. Despite recent progress, understanding the link between peptide conformational flexibility, hierarchical structures, and electron transport pathways has been challenging. Here, we use single-molecule experiments, molecular dynamics (MD) simulations, nonequilibrium Green’s function-density functional theory (NEGF-DFT), and unsupervised machine learning to understand the role of secondary structure on electron transport in peptides. Our results reveal a two-state molecular conductance behavior for peptides across several different amino acid sequences. MD simulations and Gaussian mixture modeling are used to show that this two-state molecular conductance behavior arises due to the conformational flexibility of peptide backbones, with a high-conductance state arising due to a more defined secondary structure (beta turn or 3 10 helices) and a low-conductance state occurring for extended peptide structures. These results highlight the importance of helical conformations on electron transport in peptides. Conformer selection for the peptide structures is rationalized using principal component analysis of intramolecular hydrogen bonding distances along peptide backbones. Molecular conformations from MD simulations are used to model charge transport in NEGF-DFT calculations, and the results are in reasonable qualitative agreement with experiments. Projected density of states calculations and molecular orbital visualizations are further used to understand the role of amino acid side chains on transport. Overall, our results show that secondary structure plays a key role in electron transport in peptides, which provides broad avenues for understanding the electronic properties of proteins.
Science & Technology - Other Topics↗
Secondary structure in solution of two anti-HIV-1 hammerhead ribozymes as investigated by two-dimensional 1H 500 MHz NMR spectroscopy in water
Two hammerhead chimeric RNA/DNA ribozymes (HRz) were synthesized in pure form. Both were 30 nucleotides long, and the sequences were such that they could be targeted to cleave the HIV-1 gag RNA. Named HRz-W and HRz-M, the former had its invariable core region conserved, the latter had a uridine in the invariable region replaced by a guanine. Their secodary structures were determined by 2D NOESY 1H 500 MHz NMR spectroscopy in 90% water and 10% D2(0), following the imino protons. The data show that both HRz-M and HRz-W form identical secondary structures with stem regions consisting of continuous stacks of AT and GT pairs. An energy minimized computer model of this stem region is provided. The results suggest that the loss of catalytic activity that is known to result when an invariant core residue is replaced is not related to the secondary structure of the ribozymes in the absence of substrate.
NASA Discipline Exobiology↗
GMFOLD: Subgraph matching for high-throughput DNA-aptamer secondary structure classification and machine learning interpretability
Aptamers are oligonucleotide receptors that bind to their targets with high affinity. Here, we consider aptamers comprised of single-stranded DNA that undergo target-binding-induced conformational changes, giving rise to unique secondary and tertiary structures. Given a specific aptamer primary sequence, there are well-established computational tools (notably mfold) to predict the secondary structure via free energy minimization algorithms. While mfold generates secondary structures for individual sequences, there is a need for a high-throughput process whereby thousands of DNA structures can be predicted in real-time for use in an interactive setting, when combined with aptamer selections that generate candidate pools that are too large to be experimentally interrogated. We developed a new Python code for high-throughput aptamer secondary structure determination (GMfold). GMfold uses subgraph matching methods to group aptamer candidates by secondary structure similarities. We also improve an open-source code, SeqFold, to incorporate subgraph matching concepts. We represent each secondary structure as a lowest-energy bipartite subgraph matching of the DNA graph to itself. These new tools enable thousands of DNA sequences to be compared based on their secondary structures, using machine-learning algorithms. This process is advantageous when analyzing sequences that arise from aptamer selections via systematic evolution of ligands by exponential enrichment (SELEX). This work is a building block for future machine-learning-informed DNA-aptamer selection processes to identify aptamers with improved target affinity and selectivity and advance aptamer biosensors and therapeutics.
Aptamer↗
Better understanding and prediction of antiviral peptides through primary and secondary structure feature importance
The emergence of viral epidemics throughout the world is of concern due to the scarcity of available effective antiviral therapeutics. The discovery of new antiviral therapies is imperative to address this challenge, and antiviral peptides (AVPs) represent a valuable resource for the development of novel therapies to combat viral infection. We present a new machine learning model to distinguish AVPs from non-AVPs using the most informative features derived from the physicochemical and structural properties of their amino acid sequences. To focus on those features that are most likely to contribute to antiviral performance, we filter potential features based on their importance for classification. These feature selection analyses suggest that secondary structure is the most important peptide sequence feature for predicting AVPs. Our Feature-Informed Reduced Machine Learning for Antiviral Peptide Prediction (FIRM-AVP) approach achieves a higher accuracy than either the model with all features or current state-of-the-art single classifiers. Understanding the features that are associated with AVP activity is a core need to identify and design new AVPs in novel systems. The FIRM-AVP code and standalone software package are available at https://github.com/pmartR/FIRM-AVP with an accompanying web application at https://msc-viz.emsl.pnnl.gov/AVPR.
59 BASIC BIOLOGICAL SCIENCES↗
What are the Principles Controlling Biomimetic Heteropolymer Secondary Structure? (Final Technical Report)
The goal of the project was to develop improved theories to understand how nonbiological oligomers could be designed to cooperatively fold into 3D structures. These studies would lay the groundwork for materials made of such molecules, making it possible to create controlled and ordered materials for electron transport, efficient protein-like catalysts that work under extreme conditions, and sensors with highly-specific chemical responsiveness. Two different simulation thrusts were investigated, one focused on programs to identify stable low energy folded structures at a coarse-level of description of oligomers, and another to calculate thermodynamics of such oligomers. We used these theories to answer several specific questions about what properties of oligomers lead to cooperative transitions, and to identify how oligomer knots could serve as secondary structure elements. We also carried out significant collaborative investigation with Dr. Samuel Gellman (UW-Madison, National Academy of Sciences member) on stability for foldamers of interest to them. Only one of the experimentally tested foldamers stably folded, which was indicated by simulations as being the most likely to fold. Finally, we developed new theoretical descriptions of foldamers, showing how cooperativity was determined primarily by the entropy difference between the folded and unfolded state. The research did not answer all questions laid out in the original proposal but laid the groundwork for later efforts to design folded oligomers materials with high switchability.
36 MATERIALS SCIENCE↗
Distinct Secondary Structures of the Leucine-Rich Repeat Proteoglycans Decorin and Biglycan: Glycosylation-Dependent Conformational Stability
Biglycan and decorin, closely related small leucine-rich repeat proteoglycans, have been overexpressed in eukaryotic cers and two major glycoforms isolated under native conditions: a proteoglycan substituted with glycosaminoglycan chains; and a core protein form secreted devoid of glycosaminoglycans. A comparative biophysical study of these glycoforms has revealed that the overall secondary structures of biglycan and decorin are different. Far-UV Circular Dichroism (CD) spectroscopy of decorin and biglycan proteoglycans indicates that, although they are predominantly Beta-sheet, biglycan has a significantly higher content of alpha-helical structure. Decorin proteoglycan and core protein are very similar, whereas the biglycan core protein exhibits closer similarity to the decorin glycoforms than to. the biglycan proteoglycan form. However, enzymatic removal of the chondroitin sulfate chains from biglycan proteoglycan does not induce a shift to the core protein structure, suggesting that the fmal form is influenced by polysaccharide addition only during biosynthesis. Fluorescence emission spectroscopy demonstrated that the single tryptophan residue, which is at a conserved position at the C-terminal domain of both biglycan and decorin, is found in similar microenvironments. This indicates that at least in this specific domain, the different glycoforms do exhibit apparent conservation of structure. Exposure of decorin and biglycan to 10 M urea resulted in an increase in fluorescent intensity, which indicates that the emission from tryptophan in the native state is quenched. Comparison of urea-induced protein unfolding curves provided further evidence that decorin and biglycan assume different structures in solution. Decorin proteoglycan and core protein unfold in a manner similar to a classic two-state model, in which there is a steep transition to an unfolded state between 1-2 M urea. The biglycan core protein also shows a similar steep transition. However, biglycan proteoglycan shows a broad unfolding transition between 1-6 M urea, probably indicating the presence of stable unfolding intermediates.
Krishnan, Priya↗
RNAcentral 2021: secondary structure integration, improved sequence search and new member databases
RNAcentral is a comprehensive database of non-coding RNA (ncRNA) sequences that provides a single access point to 44 RNA resources and >18 million ncRNA sequences from a wide range of organisms and RNA types. RNAcentral now also includes secondary (2D) structure information for >13 million sequences, making RNAcentral the world’s largest RNA 2D structure database. The 2D diagrams are displayed using R2DT, a new 2D structure visualization method that uses consistent, reproducible and recognizable layouts for related RNAs. The sequence similarity search has been updated with a faster interface featuring facets for filtering search results by RNA type, organism, source database or any keyword. This sequence search tool is available as a reusable web component, and has been integrated into several RNAcentral member databases, including Rfam, miRBase and snoDB. To allow for a more fine-grained assignment of RNA types and subtypes, all RNAcentral sequences have been annotated with Sequence Ontology terms. The RNAcentral database continues to grow and provide a central data resource for the RNA community. RNAcentral is freely available at https://rnacentral.org.
59 BASIC BIOLOGICAL SCIENCES↗
Transient local secondary structure in the intrinsically disordered C-term of the Albino3 insertase
Not Available
14 SOLAR ENERGY↗