Computational Scheme Research Articles

Automated multiconformer model building for X-ray crystallography and cryo-EM.

In their folded state, biomolecules exchange between multiple conformational states that are crucial for their function. Traditional structural biology methods, such as X-ray crystallography and cryogenic electron microscopy (cryo-EM), produce density maps that are ensemble averages, reflecting molecules in various conformations. Yet, most models derived from these maps explicitly represent only a single conformation, overlooking the complexity of biomolecular structures. To accurately reflect the diversity of biomolecular forms, there is a pressing need to shift toward modeling structural ensembles that mirror the experimental data. However, the challenge of distinguishing signal from noise complicates manual efforts to create these models. In response, we introduce the latest enhancements to qFit, an automated computational strategy designed to incorporate protein conformational heterogeneity into models built into density maps. These algorithmic improvements in qFit are substantiated by superior Rfree and geometry metrics across a wide range of proteins. Importantly, unlike more complex multicopy ensemble models, the multiconformer models produced by qFit can be manually modified in most major model building software (e.g., Coot) and fit can be further improved by refinement using standard pipelines (e.g., Phenix, Refmac, Buster). By reducing the barrier of creating multiconformer models, qFit can foster the development of new hypotheses about the relationship between macromolecular conformational dynamics and function.

Direct Numerical Analysis of Dynamic Facilitation in Glass-Forming Liquids.

We propose a computational strategy to quantify the temperature evolution of the timescales and length scales over which dynamic facilitation affects the relaxation dynamics of glass-forming liquids at low temperatures, which requires no assumption about the nature of the dynamics. In two glass models, we find that dynamic facilitation depends strongly on temperature, leading to a subdiffusive spreading of relaxation events which we characterize using a temperature-dependent dynamic exponent. We also establish that this temperature evolution represents a major contribution to the increase of the structural relaxation time.

Automated multiconformer model building for X-ray crystallography and cryo-EM

In their folded state, biomolecules exchange between multiple conformational states that are crucial for their function. Traditional structural biology methods, such as X-ray crystallography and cryogenic electron microscopy (cryo-EM), produce density maps that are ensemble averages, reflecting molecules in various conformations. Yet, most models derived from these maps explicitly represent only a single conformation, overlooking the complexity of biomolecular structures. To accurately reflect the diversity of biomolecular forms, there is a pressing need to shift toward modeling structural ensembles that mirror the experimental data. However, the challenge of distinguishing signal from noise complicates manual efforts to create these models. In response, we introduce the latest enhancements to qFit, an automated computational strategy designed to incorporate protein conformational heterogeneity into models built into density maps. These algorithmic improvements in qFit are substantiated by superior Rfree and geometry metrics across a wide range of proteins. Importantly, unlike more complex multicopy ensemble models, the multiconformer models produced by qFit can be manually modified in most major model building software (e.g., Coot) and fit can be further improved by refinement using standard pipelines (e.g., Phenix, Refmac, Buster). By reducing the barrier of creating multiconformer models, qFit can foster the development of new hypotheses about the relationship between macromolecular conformational dynamics and function.

Nanobody engineering: computational modelling and design for biomedical and therapeutic applications.

Nanobodies, the smallest functional antibody fragment derived from camelid heavy-chain-only antibodies, have emerged as powerful tools for diverse biomedical applications. In this comprehensive review, we discuss the structural characteristics, functional properties, and computational approaches driving the design and optimisation of synthetic nanobodies. We explore their unique antigen-binding domains, highlighting the critical role of complementarity-determining regions in target recognition and specificity. This review further underscores the advantages of nanobodies over conventional antibodies from a biosynthesis perspective, including their small size, stability, and solubility, which make them ideal candidates for economical antigen capture in diagnostics, therapeutics, and biosensing. We discuss the recent advancements in computational methods for nanobody modelling, epitope prediction, and affinity maturation, shedding light on their intricate antigen-binding mechanisms and conformational dynamics. Finally, we examine a direct example of how computational design strategies were implemented for improving a nanobody-based immunosensor, known as a Quenchbody. Through combining experimental findings and computational insights, this review elucidates the transformative impact of nanobodies in biotechnology and biomedical research, offering a roadmap for future advancements and applications in healthcare and diagnostics.

Verifiable Additive Homomorphic Secret Sharing with Dynamic Aggregation Support

(n,m,t)-Homomorphic Secret Sharing (HSS) allows n clients to share data secretly to m servers, which compute a function f homomorphically on the received secretly shared data while restricting the input data acquired by a collection of t servers to private ones. In Verifiable Homomorphic Secret Sharing (VHSS), if there are partially colluding malicious servers submitting erroneous computation results to the client, such erroneous computation results will be rejected by the client. In traditional static homomorphic secret sharing schemes, once a secret share of raw data is assigned to a group of servers, then all servers in the group must participate in the computation, which means that the computation has to be restarted once some servers fail to perform the task. In order to solve the above problem, we propose the first dynamic homomorphic secret sharing scheme for additive computation in this paper. In our scheme, once some servers fail, there is no need to recalculate the secret sharing but only the need to reissue the index set of servers that perform the computation, Our structure assigns more computation to the servers, which is very useful in real scenarios. In addition, we propose dynamic verifiable homomorphic secret sharing schemes based on the above schemes, which have less computational overhead compared to the existing schemes, although we sacrifice the public verifiability property. Finally, we give a detailed correctness, security, and verifiability analysis of the two proposed schemes and provide the theoretical and experimental evaluation results of the computational overhead.

Joint application of the Monte Carlo method and computational probabilistic analysis in problems of numerical modeling with data uncertainties

Abstract In this paper, we suggest joint application of computational probabilistic analysis and the Monte Carlo method for numerical stochastic modeling problems. We use all the capabilities of computational probabilistic analysis while maintaining all the advantages of the Monte Carlo method. Our approach allows us to efficiently implement a computational hybrid scheme. In this way, we reduce the computation time and present the results in the form of distributions. The crucial new points of our method are arithmetic operations on probability density functions and procedures for constructing on the probabilistic extensions. Relying on specific numerical examples of solving systems of linear algebraic equations with random coefficients, we present the advantages of our approach.

Strategies for Computer Science Education in University

The study investigated the Strategies for Computer Science Education Programme at Kogi State University, Anyigba. The purpose of the study was specifically targeting the types of computer facilities, their importance in computer education, factors militating against effective use for teaching and learning and strategies to be adopted for effective teaching and learning. Four research questions and four hypotheses guided the study. A descriptive survey design was adopted for the study. 100 computer students were purposively sampled for the study. Computer Education Checklist (CEC) and Strategies for Computer Education Questionnaire (SCEQ) were used as data collection tools. Percentage, mean and standard deviation were used to analyze the data collected. Analysis revealed that (1) the types of computer facilities available for computer education are laptops, printers, computer laboratories, desktops, monitors, CPU and Diskettes, CDs and flash (2) the benefits of computer education are that computer education programme enhances efficiency in teaching and learning, makes instruction in the class to be lively, and enhances individualization of learning among others, (3) several factors militate against computer education programmes in the study area are lack of skills, cost of the facilities, weak infrastructure, lack of relevant software, limited access to the internet and others and (5) strategies to handle the challenges above are that computer training for teachers, procurement of hardware facilities, curriculum development, and software development, maintenance of computer systems, adequate funding, and increase in government allocation to computer studies and provision of internet facilities should be used.

Development of a method for solving elliptic differential equations based on a nonlinear compact-polynomial scheme

A numerical method for solving elliptic differential equations (on unstructured computational grids) is described, which is based on a nonlinear compact-polynomial computational scheme. For this purpose, an approximate transition from the elliptic equation to the hyperbolic type of equations was carried out in the work. To find the solution of the hyperbolic version of the diffusion equation, a transition (in the vicinity of the computational cell Ωi) to a local curvilinear coordinate system was performed, a nonlinear compact-polynomial computational scheme was used (the "predictor" stage), and the control volume method was applied (the "corrector" stage). The results of initial testing (on problems of different physical nature) of the proposed numerical method are presented.

Efficient full-aperture mirror polishing method with variable orbital radius in computer-controlled optical surfacing

Optical systems in astronomy have extremely high requirements on the full-aperture surface precision and fabrication efficiency of aspherical mirrors. However, the current full-aperture optics fabrication method suffers from both fabrication and computation inefficiency. The former is caused by the isolated polishing strategy for the inner and edge regions of the mirror with different tools, while the latter is caused by the global computation strategy for the two regions. In this paper, a full-aperture mirror polishing method with the reversed strategy is proposed to solve this problem. Firstly, the dwell time of inner/edge regions are respectively calculated by the deconvolution method and the linear equations method based on the space-variant tool influence function. Therefore, both the computation cost and the edge polishing error can be reduced. Then, a fused tool path is developed to achieve variable orbital radius in the inner/edge region so the full aperture can be polished in one round. Simulations and experiments using a SiC aspherical mirror and large segmented mirrors demonstrate that the surface error can converge quickly in the full aperture. As a consequence, the full-aperture fabrication accuracy and efficiency can be greatly improved through the proposed method.

In-depth analysis of γ-CuI as an HTM for perovskite solar cells: A comprehensive DFT study of structural, elastic, mechanical, charge density, and optoelectronic properties

Herein, we employed Density Functional Theory (DFT) to comprehensively investigate pristine γ-CuI properties under two computational schemes: Generalized Gradient Approximation (GGA) and GGA + Hubbard correction. Structural stability is rigorously assessed through ground state energy optimization, complemented by a meticulous examination of elastic constants to confirm mechanical stability. Later on, we analyzed the electronic properties, as well as the optical properties, incorporating parameters such as the extinction coefficient that was low and refractive index that was high in the IR and visible regions. Notably, γ-CuI exhibits low reflectivity and absorption in the critical regions of interest. Our findings demonstrate that γ-CuI can serve as a cost-effective Hole Transporting Material (HTM), effectively reducing optical losses in perovskite solar cells.

Evolving ω-amine transaminase AtATA guided by substrate-enzyme binding free energy for enhancing activity and stability against non-natural substrates.

In the field of chiral amine synthesis, ω-amine transaminase (ω-ATA) is one of the most established enzymes capable of asymmetric amination under optimal conditions. However, the applicability of ω-ATA toward more non-natural complex molecules remains limited due to its low transamination activity, thermostability, and narrow substrate scope. Here, by employing a combined approach of computational virtual screening strategy and combinatorial active-site saturation test/iterative saturation mutagenesis strategy, we have constructed the best variant M14C3-V5 (M14C3-V62A-V116S-E117I-L118I-V147F) with improved ω-ATA from Aspergillus terreus (AtATA) activity and thermostability toward non-natural substrate 1-acetylnaphthalene, which is the ketone precursor for producing the intermediate (R)-(+)-1-(1-naphthyl)ethylamine [(R)-NEA] of cinacalcet hydrochloride, showing activity enhancement of up to 3.4-fold compared to parent enzyme M14C3 (AtATA-F115L-M150C-H210N-M280C-V149A-L182F-L187F). The computational tools YASARA, Discovery Studio, Amber, and FoldX were applied for predicting mutation hotspots based on substrate-enzyme binding free energies and to show the possible mechanism with features related to AtATA structure, catalytic activity, and stability in silico analyses. M14C3-V5 achieved 71.8% conversion toward 50 mM 1-acetylnaphthalene in a 50 mL preparative-scale reaction for preparing (R)-NEA. Moreover, M14C3-V5 expanded the substrate scope toward aromatic ketone compounds. The generated virtual screening strategy based on the changes in binding free energies has successfully predicted the AtATA activity toward 1-acetylnaphthalene and related substrates. Together with experimental data, these approaches can serve as a gateway to explore desirable performances, expand enzyme-substrate scope, and accelerate biocatalysis.IMPORTANCEChiral amine is a crucial compound with many valuable applications. Their asymmetric synthesis employing ω-amine transaminases (ω-ATAs) is considered an attractive method. However, most ω-ATAs exhibit low activity and stability toward various non-natural substrates, which limits their industrial application. In this work, protein engineering strategy and computer-aided design are performed to evolve the activity and stability of ω-ATA from Aspergillus terreus toward non-natural substrates. After five rounds of mutations, the best variant, M14C3-V5, is obtained, showing better catalytic efficiency toward 1-acetylnaphthalene and higher thermostability than the original enzyme, M14C3. The robust combinational variant acquired displayed significant application value for pushing the asymmetric synthesis of aromatic chiral amines to a higher level.

Free-energy calculations in condensed matter: from early challenges to the advent of umbrella sampling

The investigation of condensed matter transformations hinges on the precision of free-energy calculations. This article charts the evolution of molecular simulations, tracing their development from the techniques of the early 1960s, through the emergence of free-energy calculations toward the end of the decade, and leading to the advent of umbrella sampling in 1977. The discussion explores the inherent challenges and limitations of early simulational endeavors, such as the struggle with accurate phase-space sampling and the need for innovative solutions like importance sampling and multistage sampling methods. Taken together, the initial hurdles and subsequent adoption of advanced techniques exemplify the leap from analytical methods to effective computational strategies that enabled more reliable simulations. Further analysis of this narrative reveals the methodological breakthroughs as well as the setbacks that transformed the theoretical and practical understanding of condensed matter phenomena. A follow-up study will examine the shifts in free-energy calculations from the late 1970s into the 1980s.

A Computational Strategy for the Rapid Identification and Ranking of Patient-Specific T Cell Receptors Bound to Neoantigens.

T cell receptor (TCR) recognition of a peptide-major histocompatibility complex (pMHC) is crucial for adaptive immune response. The identification of therapeutically relevant TCR-pMHC protein pairs is a bottleneck in the implementation of TCR-based immunotherapies. The ability to computationally design TCRs to target a specific pMHC requires automated integration of next-generation sequencing, protein-protein structure prediction, molecular dynamics, and TCR ranking. A pipeline to evaluate patient-specific, sequence-based TCRs to a target pMHC is presented. Using the three most frequently expressed TCRs from 16 colorectal cancer patients, the protein-protein structure of the TCRs to the target CEA peptide-MHC is predicted using Modeller and ColabFold. TCR-pMHC structures are compared using automated equilibration and successive analysis. ColabFold generated configurations require an ≈2.5× reduction in equilibration time of TCR-pMHC structures compared to Modeller. The structural differences between Modeller and ColabFold are demonstrated by root mean square deviation (≈0.20nm) between clusters of equilibrated configurations, which impact the number of hydrogen bonds and Lennard-Jones contacts between the TCR and pMHC. TCR ranking criteria that may prioritize TCRs for evaluation of in vitro immunogenicity are identified, and this ranking is validated by comparing to state-of-the-art machine learning-based methods trained to predict the probability of TCR-pMHC binding.

An adaptive simulated annealing-based computational offloading scheme in UAV-assisted MEC networks

Mobile edge computing (MEC) is an advanced technology that enables fifth-generation (5G) applications. It uses a mechanism to offload computation from mobile devices (MDs) to edge servers at the access point (AP) to improve the quality of computation. By leveraging the strengths of unmanned aerial vehicles (UAVs), we can install edge servers on UAVs to support task offloading. However, this is constrained by the limited computational resources of UAVs and high energy consumption. Due to the complexity of such architecture, the joint optimization of energy consumption and delay by applying classical optimization algorithms cannot work well either. So far, there is no research work that addresses the problem of computation offloading in UAV-based MEC networks considering the UAV-AP-MD architecture that is well applicable in 5G scenarios; this motivates us to propose this work. We first formulate this problem as an optimization problem and then develop an adaptive simulated annealing-based method for joint optimization of energy consumption and delay. We design a mechanism to dynamically increase the cooling rate as a function of decreasing temperature to achieve better convergence, and implement a task queue for MDs and servers. Finally, we perform numerical simulations and find that the proposed method reduces the energy consumption (17%) and delay (50%) of MDs and UAV while it has the best task dropped rate (50%) and fairness (4.2%) compared to other known methods.

Priority-weight-based computing and spectrum resource scheduling for dependent tasks in EON-supported computing first networks

The computing first network (CFN) supported by the elastic optical network (EON) is proposed as an innovative information infrastructure, where end users can access computing resources on demand. However, since the link capacity is limited, the network capacity bottleneck may cause task offloading failures even with sufficient computing resources. This paper proposes a cost-efficient computing and spectrum resource scheduling scheme to solve the above problem. The goal is to determine offloading decisions for dependent tasks by minimizing the completion delay and the energy consumption on computing nodes powered by non-green energy (i.e., non-green energy consumption). A priority-weight-based computing and spectrum resource scheduling (PW-CSRS) algorithm is proposed, which can sort the execution order of sub-tasks and optimize computing node selection and spectrum allocation. PW-CSRS is compared with three benchmarks in the 52-node and 33-node systems, and simulation results show that PW-CSRS can effectively improve the acceptance ratio and reduce non-green energy consumption.

Application of bi-directional evolutionary structural optimization to the design of an innovative pedestrian bridge

With rapid advances in design methods and structural analysis techniques, computational generative design strategies have been adopted more widely in the field of architecture and engineering. As a performance-based design technique to find out the most efficient structural form, topology optimization provides a powerful tool for designers to explore lightweight and elegant structures. Building on this background, this study proposes an innovative pedestrian bridge design, which covers the process from conceptualization to detailed design implementation. This pedestrian bridge, with a main span of 152 m, needs to meet some unique architectural requirements, while addressing multiple engineering challenges. Aiming to reduce the depth of the girder but still meeting the load-carrying capacity requirements, the superstructure of this bridge adopts a variable-depth spinal-shaped girder in the center of its deck, thus forming an elegant curving facade, from which one pathway cantilevers on either side. At one end of the bridge, given considerable elevation difference between the bridge deck and the ground, a two-level Fibonacci-type spiral-shaped bicycle ramp is provided. The superstructure is supported by a series of organic tree-shaped branching piers resulting from the topology optimization. The ingenious design for the elegant profile of the bicycle ramp generates an enjoyable and dynamic crossing experience, with scenic views in all directions. By virtue of technological innovation, the pedestrian bridge is expected to create an iconic, cost-effective, and low-maintenance solution. A brief overview of the theoretical background of the bi-directional evolutionary structure optimization (BESO) and the multi-material BESO approach is also offered in this paper, while the construction requirements and challenges, conceptual development process, form-finding strategy, detailed design, and construction method of the bridge are presented.

Adaptive region algorithm based on a ternary optical computer

The adaptive region algorithm is an improved compression algorithm based on Huffman coding. Because of the large number of rules for dividing regions in the algorithm, there are problems such as high computing costs, slow speed, and low compression efficiency. To address these problems, this paper investigates the adaptive region algorithm based on a ternary optical computer (TOC) combined with the characteristics of a ternary optical computer, such as many data bits, high parallelism, and three-valued coding. According to the characteristics of TOC three-valued coding, this paper designs a three-valued character coding scheme that can effectively shorten the coding length of characters by changing the original coding rules and further improve the compression efficiency of the adaptive region algorithm. Furthermore, in conjunction with the advantages of TOC enabling parallel computation, this paper presents an efficient computational scheme capable of effectively improving computational efficiency during the process of region partitioning. Through case studies, the compression efficiency and computational efficiency of the adaptive region algorithm implemented on TOC and an electronic computer were analyzed, respectively. It was found that the compression efficiency of the TOC-based algorithm is 50.4%, while that of the electronic-computer-based algorithm is only 36%. In the comparison of computational efficiency, the computational time complexity of TOC is O(n), whereas that of the electronic computer (EC) is O(n2). Finally, it is concluded through experimental validation that the TOC-based adaptive region compression algorithm performs well in terms of computational performance and compression efficiency, giving full play to the three-valued coding characteristics of TOC-based as well as the advantages of being able to realize parallel computation.

Computational single-cell methods for predicting cancer risk.

Despite recent biotechnological breakthroughs, cancer risk prediction remains a formidable computational and experimental challenge. Addressing it is critical in order to improve prevention, early detection and survival rates. Here, I briefly summarize some key emerging theoretical and computational challenges as well as recent computational advances that promise to help realize the goals of cancer-risk prediction. The focus is on computational strategies based on single-cell data, in particular on bottom-up network modeling approaches that aim to estimate cancer stemness and dedifferentiation at single-cell resolution from a systems-biological perspective. I will describe two promising methods, a tissue and cell-lineage independent one based on the concept of diffusion network entropy, and a tissue and cell-lineage specific one that uses transcription factor regulons. Application of these tools to single-cell and single-nucleus RNA-seq data from stages prior to invasive cancer reveal that they can successfully delineate the heterogeneous inter-cellular cancer-risk landscape, identifying those cells that are more likely to turn cancerous. Bottom-up systems biological modeling of single-cell omic data is a novel computational analysis paradigm that promises to facilitate the development of preventive, early detection and cancer-risk prediction strategies.

Deciphering the genetic code of neuronal type connectivity through bilinear modeling.

Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset of Caenorhabditis elegans, our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.

Deciphering the genetic code of neuronal type connectivity through bilinear modeling

Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset of Caenorhabditis elegans, our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.