Current Molecular Models Research Articles

Conformational Space Profiling Enhances Generic Molecular Representation for AI-Powered Ligand-Based Drug Discovery.

The molecular representation model is a neural network that converts molecular representations (SMILES, Graph) into feature vectors, and is an essential module applied across a wide range of artificial intelligence-driven drug discovery scenarios. However, current molecular representation models rarely consider the three-dimensional conformational space of molecules, losing sight of the dynamic nature of small molecules as well as the essence of molecular conformational space that covers the heterogeneity of molecule properties, such as the multi-target mechanism of action, recognition of different biomolecules, dynamics in cytoplasm and membrane. In this study, a new model named GeminiMol is proposed to incorporate conformational space profiles into molecular representation learning, which extracts the feature of capturing the complicated interplay between the molecular structure and the conformational space. Although GeminiMol is pre-trained on a relatively small-scale molecular dataset (39290 molecules), it shows balanced and superior performance not only on 67 molecular properties predictions but also on 73 cellular activity predictions and 171 zero-shot tasks (including virtual screening and target identification). By capturing the molecular conformational space profile, the strategy paves the way for rapid exploration of chemical space and facilitates changing paradigms for drug design.

The Past, Present, and Future of a Human T-Cell Leukemia Virus Type 1 Vaccine.

Human T-cell leukemia virus type 1 (HTLV-1) is an oncogenic human retrovirus which causes a lifelong infection. An estimated 5–10 million persons are infected with HTLV-1 worldwide – a number which is likely higher due to lack of reliable epidemiological data. Most infected individuals remain asymptomatic; however, a portion of HTLV-1-positive individuals will develop an aggressive CD4+ T-cell malignancy called adult T-cell leukemia/lymphoma (ATL), or a progressive neurodegenerative disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Few treatment options exist for HAM/TSP outside of palliative care and ATL carries an especially poor prognosis given the heterogeneity of the disease and lack of effective long-term treatments. In addition, the risk of HTLV-1 disease development increases substantially if the virus is acquired early in life. Currently, there is no realistic cure for HTLV-1 infection nor any reliable measure to prevent HTLV-1-mediated disease development. The severity of HTLV-1-associated diseases (ATL, HAM/TSP) and limited treatment options highlights the need for development of a preventative vaccine or new therapeutic interventions. This review will highlight past HTLV-1 vaccine development efforts, the current molecular tools and animal models which might be useful in vaccine development, and the future possibilities of an effective HTLV-1 vaccine.

Abstract B07: A long noncoding RNA-based genomic classifier identifies a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis

Abstract Background: Muscle-invasive bladder cancer (MIBC) is a heterogeneous disease and gene expression profiling has identified different molecular subtypes, each having distinct biologic and clinicopathologic characteristics. Subtyping MIBC has primarily been messenger RNA (mRNA)-based, although noncoding RNAs, including long noncoding RNAs (lncRNAs), have potential utility in providing additional resolution to current molecular subtyping models. Materials and Methods: The expression profiles of over 6,000 lncRNAs were quantified from whole-transcriptome microarray data of a MIBC patient cohort treated by neoadjuvant chemotherapy (NAC) and radical cystectomy (N=223). Unsupervised consensus clustering of the most highly variant lncRNAs identified a four-cluster solution, which was further characterized using a panel of MIBC biomarkers, gene signatures, and survival analysis. The four-cluster consensus was validated using the publicly available The Cancer Genome Atlas (TCGA) radical cystectomy cohort (N=405). A single-sample genomic classifier (GC) was trained using ridge-penalized logistic regression and then validated in two independent patient cohorts (N=255 and N=94). Results: In the NAC and TCGA cohorts, survival analysis of a lncRNA-based consensus cluster solution revealed a lncRNA-cluster (LC3) with strikingly good prognosis that was enriched for tumors of the luminal-papillary mRNA subtype. In both cohorts, the luminal-papillary tumors from this cluster (LPL-C3) were clinically less aggressive than other luminal-papillary tumors. Patients having LPL-C3 tumors were younger and had more frequent organ-confined, node-negative disease than other luminal-papillary tumors. LPL-C3 tumors were characterized by enhanced FGFR3 pathway activity, wild-type P53 expression, and robust SHH signaling. In the TCGA cohort, LPL-C3 tumors were also enriched for FGFR3 mutations and depleted for TP53 and RB1 mutations. A GC trained to identify these LPL-C3 patients showed robust performance in two validation cohorts. Conclusions: Using lncRNA expression profiling, we identified a biologically distinct subgroup of luminal-papillary MIBC with less-aggressive molecular characteristics and favorable prognosis. These data suggest that lncRNAs can provide additional information in resolving higher-resolution subtypes for more precise patient management strategies. Citation Format: Joep J. de Jong, Yang Liu, Roland Seiler, A. Gordon Robertson, Michiel S. van der Heijden, Jonathan L. Wright, James Douglas, Marc Dall'Era, Simon J. Crabb, Bas W.G. van Rhijn, Kim E.M. van Kessel, Elai Davicioni, Yair Lotan, Ellen C. Zwarthoff, Peter C. Black, Joost L. Boormans, Ewan A. Gibb. A long noncoding RNA-based genomic classifier identifies a subset of luminal muscle-invasive bladder cancer patients with favorable prognosis [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr B07.

Electron Paramagnetic Resonance Measurements of Four Nitroxide Probes in Supercooled Water Explained by Molecular Dynamics Simulations.

Electron paramagnetic resonance (EPR) measurements of the rotational diffusion of small nitroxide probes have been demonstrated to be a powerful technique for experimentally investigating the properties of supercooled liquids, such as water. However, since only the rotational diffusion of the probe molecules is measured and EPR measurements are indirect, it is not clear what the relationship between the behavior of water and the probe molecule is. To address this, we have performed molecular dynamics simulations of four nitroxide probes in TIP4P-Ew and OPC water models to directly compare with EPR experiments and to determine the behavior of the water and the underlying microscopic coupling between the water and the probes. In all, 200 ns simulations were run for 23 temperatures between 253 and 283 K for all four probes with each water model for an aggregate of 36.8 μs of simulation time. Simulations for both water models systematically underestimated the rotational diffusion coefficients for both water and probes, though OPC simulations were generally in better agreement with the experiments than TIP4P-Ew simulations. Despite this, when the temperature dependence of the data was fit to a power law, fit parameters for TIP4P-Ew were generally in better agreement with the experiments than OPC. For probe molecules, the singular temperature was found to be T0 = 226.5 ± 0.4 K from experiments, T0 = 208 ± 2 K for OPC water, and T0 = 215 ± 2 K for TIP4P-Ew water. While for water molecules, the singular temperature was found to be T0 = 220.3 ± 0.2 K from experiments, T0 = 208 ± 2 K for OPC water, and T0 = 220 ± 1 K for TIP4P-Ew water. Systematic underestimation of the rotational diffusion coefficients was most pronounced at lower temperatures and was clearly observed in changes to the Arrhenius activation energy. Above the maximum density temperature of Tρmax = 277 K, an activation energy of EA ≈ 16.7 kJ/mol was observed for the probes from experiments, while OPC had EA ≈ 15.2 kJ/mol and TIP4P-Ew had EA ≈ 14.6 kJ/mol. Below the maximum density temperature, the activation energy jumped to EA ≈ 32.5 kJ/mol for experiments but only EA ≈ 23 kJ/mol for OPC and EA ≈ 22 kJ/mol for TIP4P-Ew. In all cases, we saw good agreement between the behavior of the probe molecules and water. To understand why, we calculated the average number of hydrogen bonds between the probe molecules and water. From this, we were able to explain the rotational diffusion times for all of the probes. These results show that current molecular models are sufficient to capture physical phenomena observed with EPR and to help elucidate why the probes provide accurate insights into the behavior of supercooled water.

Rationality evaluation index of asphalt molecular model

In terms of the diversity and complexity of current molecular models of asphalt, this paper proposes the solubility parameter as the evaluation index of asphalt component rationality. The solubility parameters of 22 asphaltenes average molecular models, 3 aromatics average molecular models, 3 saturates average molecular models and 4 resins average molecular models were calculated, according to the principle of similar compatibility, reasonable molecular models of the average asphalt component were selected. A molecular model of asphalt was established based on a four-component test. The glass transition temperature was used as the evaluation index, and the temperature difference between the molecular simulation and the DSC test was less than 1 °C.

Advances in neurodegenerative and psychiatric imaging: introductory editorial.

Advances in neurodegenerative and psychiatric imaging: introductory editorial.

Type IV pili: dynamics, biophysics and functional consequences.

The surfaces of many bacteria are decorated with long, exquisitely thin appendages called type IV pili (T4P), dynamic filaments that are rapidly polymerized and depolymerized from a pool of pilin subunits. Cycles of pilus extension, binding and retraction enable T4P to perform a phenomenally diverse array of functions, including twitching motility, DNA uptake and microcolony formation. On the basis of recent developments, a comprehensive understanding is emerging of the molecular architecture of the T4P machinery and the filament it builds, providing mechanistic insights into the assembly and retraction processes. Combined microbiological and biophysical approaches have revealed how T4P dynamics influence self-organization of bacteria, how bacteria respond to external stimuli to regulate T4P activity for directed movement, and the role of T4P retraction in surface sensing. In this Review, we discuss the T4P machine architecture and filament structure and present current molecular models for T4P dynamics, with a particular focus on recent insights into T4P retraction. We also discuss the functional consequences of T4P dynamics, which have important implications for bacterial lifestyle and pathogenesis.

The syndrome of proximal femur, fibula, and midline metatarsal long bone deficiencies.

Human lower limb congenital long bone deficiencies cluster primarily at three distinct skeletal locations. Proximal femoral and fibular reductions are known phenomena. In contrast, midline metatarsal deficiencies have been misrepresented as lateral. The popular term, "fibular hemimelia," is inaccurate and its use is discouraged. All three locations correspond to discrete sites of evolving angiogenesis during transition from a single embryonic axial limb artery to the familiar and complex adult arterial pattern. Initiation of bone formation of cartilaginous primordia of the long bones at all three sites occurs in proximity to, and depends upon, successful invasion by mature nutrient vessels, formed during the 6th and 7th weeks of embryonic development. The adult arterial pattern is fully established by 8th embryonic week. Arterial transitions occur later in development, around the time of cessation of the molecular processes of patterning/specification of the embryonic limb. Evidence of flawed embryonic arterial transitions, involving missing, reduced and/or retained primitive vessels in association with congenital skeletal reductions have been demonstrated at all three sites. Current molecular models of limb development do not explain the distribution of this triad of congenital skeletal reductions. These dysmorphologies are most accurately described as post-specification errors of limb development. Recognition of this distinctive model of limb maldevelopment demands further investigation to create a more exact taxonomy, one consistent with both clinical and molecular criteria. The established terminologies originated by Frantz and O'Rahilly should be reconsidered or abandoned. Designation of this clinical triad as a syndrome of proximal femur, fibula, and midline metatarsal dystrophisms initiates that endeavor.

Ribosomopathies: There's strength in numbers.

Ribosomopathies are a group of human disorders most commonly caused by ribosomal protein haploinsufficiency or defects in ribosome biogenesis. These conditions manifest themselves as physiological defects in specific cell and tissue types. We review current molecular models to explain ribosomopathies and attempt to reconcile the tissue specificity of these disorders with the ubiquitous requirement for ribosomes in all cells. Ribosomopathies as a group are diverse in their origins and clinical manifestations; we use the well-described Diamond-Blackfan anemia (DBA) as a specific example to highlight some common features. We discuss ribosome homeostasis as an overarching principle that governs the sensitivity of specific cells and tissue types to ribosomal protein mutations. Mathematical models and experimental insights rationalize how even subtle shifts in the availability of ribosomes, such as those created by ribosome haploinsufficiency, can drive messenger RNA-specific effects on protein expression. We discuss recently identified roles played by ribosome rescue and recycling factors in regulating ribosome homeostasis.

EQTLs Regulating Transcript Variations Associated with Rapid Internode Elongation in Deepwater Rice.

To avoid low oxygen, oxygen deficiency or oxygen deprivation, deepwater rice cultivated in flood planes can develop elongated internodes in response to submergence. Knowledge of the gene regulatory networks underlying rapid internode elongation is important for an understanding of the evolution and adaptation of major crops in response to flooding. To elucidate the genetic and molecular basis controlling their deepwater response we used microarrays and performed expression quantitative trait loci (eQTL) and phenotypic QTL (phQTL) analyses of internode samples of 85 recombinant inbred line (RIL) populations of non-deepwater (Taichung 65)- and deepwater rice (Bhadua). After evaluating the phenotypic response of the RILs exposed to submergence, confirming the genotypes of the populations, and generating 188 genetic markers, we identified 10,047 significant eQTLs comprised of 2,902 cis-eQTLs and 7,145 trans-eQTLs and three significant eQTL hotspots on chromosomes 1, 4, and 12 that affect the expression of many genes. The hotspots on chromosomes 1 and 4 located at different position from phQTLs detected in this study and other previous studies. We then regarded the eQTL hotspots as key regulatory points to infer causal regulatory networks of deepwater response including rapid internode elongation. Our results suggest that the downstream regulation of the eQTL hotspots on chromosomes 1 and 4 is independent, and that the target genes are partially regulated by SNORKEL1 and SNORKEL2 genes (SK1/2), key ethylene response factors. Subsequent bioinformatic analyses, including gene ontology-based annotation and functional enrichment analysis and promoter enrichment analysis, contribute to enhance our understanding of SK1/2-dependent and independent pathways. One remarkable observation is that the functional categories related to photosynthesis and light signaling are significantly over-represented in the candidate target genes of SK1/2. The combined results of these investigations together with genetical genomics approaches using structured populations with a deepwater response are also discussed in the context of current molecular models concerning the rapid internode elongation in deepwater rice. This study provides new insights into the underlying genetic architecture of gene expression regulating the response to flooding in deepwater rice and will be an important community resource for analyses on the genetic basis of deepwater responses.

Effective Polarization in Pairwise Potentials at the Graphene-Electrolyte Interface.

At the graphene-electrolyte interface, the polarizability of both the surface and the solution plays a major role in defining the interfacial structure and dynamics of the ions. Current molecular models predict different ion adsorption behavior at the interface depending on whether surface or solution polarization is included in the model. Here, we propose a simple method to parametrize the ion-carbon interaction from density functional theory, implicitly modeling the solution using the conductor-like polarizable continuum model. The new model simultaneously takes into account the polarizability of both the graphene sheet and the solution without the need to use time-consuming polarizable potentials and can predict the ion adsorption trend so far only achievable using first-principles simulations. Simulations performed with 1 M electrolyte solutions of different ions show that cations are strongly adsorbed onto the graphene surface with a trend (Li+ < Na+ < K+) opposite to that predicted by the gas-phase calculations and different from that obtained from the single-ion simulations.

Mechanisms, applications, and perspectives of antiviral RNA silencing in plants.

Viral diseases of plants cause important economic losses due to reduction in crop quality and quantity to the point of threatening food security in some countries. Given the reduced availability of natural sources, genetic resistance to viruses has been successfully engineered for some plant-virus combinations. A sound understanding of the basic mechanisms governing plant-virus interactions, including antiviral RNA silencing, is the foundation to design better management strategies and biotechnological approaches to engineer and implement antiviral resistance in plants. In this review, we present current molecular models to explain antiviral RNA silencing and its application in basic plant research, biotechnology and genetic engineering.

To Grow is not Enough: The Impact of Cell Response Time on Fitness

Recent results showing the magnitude of fluctuations in individual cell division times to be highly concerted across widely varying cell types and environmental conditions have been difficult to explain with current molecular cell cycle models. Here we present a phenomenological model for the regulation of cellular division time distributions determining both bulk growth rate and ensemble fluctuations. A cellular “fitness” function is proposed which incorporates not only growth rate, which is maximized when fluctuations are minimized, but also ensemble response time to environmental stimulus which decreases for increasing fluctuations. Single cell division data is collected on a population of isogenic cells subjected to varying environmental stimuli and compared to the model. Our findings suggest that even cells exhibiting exponential growth do not optimize their “fitness” through growth rate alone, but also response time.

Lipid transport in the lactating mammary gland.

Mammalian cells depend on phospholipid (PL) and fatty acid (FA) transport to maintain membrane structure and organization, and to fuel and regulate cellular functions. In mammary glands of lactating animals, copious milk secretion, including large quantities of lipid in some species, requires adaptation and integration of PL and FA synthesis and transport processes to meet secretion demands. At present few details exist about how these processes are regulated within the mammary gland. However, recent advances in our understanding of the structural and molecular biology of membrane systems and cellular lipid trafficking provide insights into the mechanisms underlying the regulation and integration of PL and FA transport processes the lactating mammary gland. This review discusses the PL and FA transport processes required to maintain the structural integrity and organization of the mammary gland and support its secretory functions within the context of current molecular and cellular models of their regulation.

The principles of wound healing

Wound healing is an ever-changing field, as new insights are made into its mechanisms through basic science research, thus driving development of new therapies. In this paper, we present the current molecular models of wound healing and scar formation in the three phases: inflammation, proliferation and remodeling. New cellular signaling pathways such as mechanotransduction through the transforming growth factor-beta and integrin pathways have opened up various targets for wound therapy. Other therapies such as negative pressure devices and anti-microbial peptides are being improved as more data becomes available. Cutting edge treatments in gene therapy like Regranex are under heavy investigation, as are various treatments whose molecular mechanisms remain to be elucidated such as electrostimulation and Substance P. A promising area in wound treatment research is the use of bone marrow derived stem cell therapy, where research in animal models has shown these stem cells are able to differentiate into kera...

Vitamin E and Disease Risk: Research Focus Turns on Genetic Polymorphisms and Molecular Mechanisms

Copyright: © 2012 Zingg JM. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. A possible preventive effect of supplementation with vitamin E (α-tocopherol) against atherosclerosis and other diseases such as cancer and neurodegeneration has been addressed in many studies (reviewed in [1-3]). Whereas in most animal studies vitamin E supplementation reduces cardiovascular disease (CVD), human randomized clinical trials and epidemiologic studies have reported both positive and negative outcomes (reviewed in [2]). Meta-analyses of the clinical studies even suggested an increased all-cause mortality with high doses of vitamin E supplementation [4,5], although other more recent studies did not confirm this [6,7]. Similar to that, a significant increase in prostate cancer risk was observed in the recent follow-up study of the Selenium and Vitamin E Cancer Prevention Trial (SELECT) [8], whereas a preventive effect of vitamin E was observed in a study on nonalcoholic steatohepatitis (NASH) in adults without diabetes [9]. Intriguingly, based on the molecular properties of vitamin E as free radical scavenger, some of these results were not expected, suggesting that the current molecular models of vitamin E action may need to be revised.

The adsorption of xyloglucan on cellulose: effects of explicit water and side chain variation

The interaction between para-crystalline cellulose and the cross-linking glycan xyloglucan (XG) plays a central role for the strength and extensibility of plant cell walls. The coating of XGs on cellulose surfaces is believed to be one of the most probable interaction patterns. In this work, the effects of explicit water and side chain variation on the adsorption of XGs on cellulose are investigated by means of atomistic molecular dynamics simulations. The adsorption properties are studied in detail for three XGs on cellulose Iβ 1–10 surface in aqueous environment, namely GXXXGXXXG, GXXLGXXXG, and GXXFGXXXG, which differ in the length and composition of one side chain. Our work shows that when water molecules are included in the theoretical model, the total interaction energies between the adsorbed XGs and cellulose are considerably smaller than in vacuo. Furthermore, in water environment the van der Waals interactions prevail over the electrostatic interactions in the adsorption. Variation in one side chain does not have significant influence on the interaction energy and the binding affinity, but does affect the equilibrium structural properties of the adsorbed XGs to facilitate the interaction between both the backbone and the side chain residues with the cellulose surface. Together, this analysis provides new insights into the nature of the XG–cellulose interaction, which helps to further refine current molecular models of the composite plant cell wall.

Effects of Ultraviolet-A and Riboflavin on the Interaction of Collagen and Proteoglycans during Corneal Cross-linking

Corneal cross-linking using riboflavin and ultraviolet-A (RFUVA) is a clinical treatment targeting the stroma in progressive keratoconus. The stroma contains keratocan, lumican, mimecan, and decorin, core proteins of major proteoglycans (PGs) that bind collagen fibrils, playing important roles in stromal transparency. Here, a model reaction system using purified, non-glycosylated PG core proteins in solution in vitro has been compared with reactions inside an intact cornea, ex vivo, revealing effects of RFUVA on interactions between PGs and collagen cross-linking. Irradiation with UVA and riboflavin cross-links collagen α and β chains into larger polymers. In addition, RFUVA cross-links PG core proteins, forming higher molecular weight polymers. When collagen type I is mixed with individual purified, non-glycosylated PG core proteins in solution in vitro and subjected to RFUVA, both keratocan and lumican strongly inhibit collagen cross-linking. However, mimecan and decorin do not inhibit but instead form cross-links with collagen, forming new high molecular weight polymers. In contrast, corneal glycosaminoglycans, keratan sulfate and chondroitin sulfate, in isolation from their core proteins, are not cross-linked by RFUVA and do not form cross-links with collagen. Significantly, when RFUVA is conducted on intact corneas ex vivo, both keratocan and lumican, in their natively glycosylated form, do form cross-links with collagen. Thus, RFUVA causes cross-linking of collagen molecules among themselves and PG core proteins among themselves, together with limited linkages between collagen and keratocan, lumican, mimecan, and decorin. RFUVA as a diagnostic tool reveals that keratocan and lumican core proteins interact with collagen very differently than do mimecan and decorin.

Glass Transition Behavior: A Generic Phenomenological Approach

This paper surveys phenomenological and atomistic methods by which glass transition can be described. A new generic phenomenological approach to the study of glass transition as an irreversible process is then derived and fully used. This new approach describes the kinetics and thermodynamics of vitrification as a real, nonequilibrium process of structural arrest, entropy freeze, and entropy production. The temperature dependence of the thermodynamic functions is constructed as it corresponds to the principles of both classical and irreversible thermodynamics and to the experimental evidence obtained through long years of glass‐science research. The developed generic phenomenological approach complements, expands, and quantitatively corrects the approximations of F. Simon, which have been the principal method in glass science thermodynamics for over 80 years. Using the same generic phenomenological approach, new and classical models for describing the glass transition are examined in terms of past and current molecular statistical models. The methods derived in the present phenomenological approach indicate alternative ways to synthesize glasses with new properties and technical applications by changing the rates of structural arrest at vitrification, as they are determined by cooling rate, pressure increase, or alteration of the strength of electric or magnetic fields.

Structure and function of the molecular chaperone Hsp104 from yeast

The molecular chaperone Hsp104 plays a central role in the clearance of aggregates after heat shock and the propagation of yeast prions. Hsp104's disaggregation activity and prion propagation have been linked to its ability to resolubilize or remodel protein aggregates. However, Hsp104 has also the capacity to catalyze protein aggregation of some substrates at specific conditions. Hence, it is a molecular chaperone with two opposing activities with respect to protein aggregation. In yeast models of Huntington's disease, Hsp104 is required for the aggregation and toxicity of polyglutamine (polyQ), but the expression of Hsp104 in cellular and animal models of Huntington's and Parkinson's disease protects against polyQ and alpha-synuclein toxicity. Therefore, elucidating the molecular determinants and mechanisms underlying the ability of Hsp104 to switch between these two activities is of critical importance for understanding its function and could provide insight into novel strategies aimed at preventing or reversing the formation of toxic protein aggregation in systemic and neurodegenerative protein misfolding diseases. Here, we present an overview of the current molecular models and hypotheses that have been proposed to explain the role of Hsp104 in modulating protein aggregation and prion propagation. The experimental approaches and the evidences presented so far in relation to these models are examined. Our primary objective is to offer a critical review that will inspire the use of novel techniques and the design of new experiments to proceed towards a qualitative and quantitative understanding of the molecular mechanisms underlying the multifunctional properties of Hsp104 in vivo.