scholarly journals Minimum epistasis interpolation for sequence-function relationships

2019 ◽  
Author(s):  
Juannan Zhou ◽  
David M. McCandlish
Keyword(s):  
Predictive Power ◽  
Biological Function ◽  
Fitness Landscape ◽  
Complex Structure ◽  
Genetic Interactions ◽  
Massively Parallel ◽  
Single Experiment ◽  
Complicated Manner ◽  
Function Relationship ◽  
Insight Into

AbstractMassively parallel phenotyping assays have provided unprecedented insight into how multiple mutations combine to determine biological function. While these assays can measure phenotypes for thousands to millions of genotypes in a single experiment, in practice these measurements are not exhaustive, so that there is a need for techniques to impute values for genotypes whose phenotypes are not directly assayed. Here we present a method based on the idea of inferring the least epistatic possible sequence-function relationship compatible with the data. In particular, we infer the reconstruction in which mutational effects change as little as possible across adjacent genetic backgrounds. Although this method is highly conservative and has no tunable parameters, it also makes no assumptions about the form that genetic interactions take, resulting in predictions that can behave in a very complicated manner where the data require it but which are nearly additive where data is sparse or absent. We apply this method to analyze a fitness landscape for protein G, showing that our technique can provide a substantially less epistatic fit to the landscape than standard methods with little loss in predictive power. Moreover, our analysis reveals that the complex structure of epistasis observed in this dataset can be well-understood in terms of a simple qualitative model consisting of three fitness peaks where the landscape is locally additive in the vicinity of each peak.

Structural glycobiology: How to gain insight into the structure-function relationship

1997 ◽  
Vol 69 (9) ◽  
pp. 1875-1878 ◽  
Author(s):  
J. F. G. Vliegenthart
Keyword(s):  
Structure Function ◽  
Structure Function Relationship ◽  
Function Relationship ◽  
Insight Into

scholarly journals Systematic characterization and genetic interaction analysis of adhesins in Candida albicans virulence

2020 ◽  
Author(s):  
Sierra Rosiana ◽  
Liyang Zhang ◽  
Grace H. Kim ◽  
Alexey V. Revtovich ◽  
Arjun Sukumaran ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Genetic Interaction ◽  
Interaction Analysis ◽  
Genetic Interactions ◽  
Fungal Virulence ◽  
C Elegans ◽  
Adhesin Proteins ◽  
Insight Into

AbstractCandida albicans is a microbial fungus that exists as a commensal member of the human microbiome and an opportunistic pathogen. Cell surface-associated adhesin proteins play a crucial role in C. albicans’ ability to undergo cellular morphogenesis, develop robust biofilms, colonize, and cause infection in a host. However, a comprehensive analysis of the role and relationships between these adhesins has not been explored. We previously established a CRISPR-based platform for efficient generation of single- and double-gene deletions in C. albicans, which was used to construct a library of 144 mutants, comprising 12 unique adhesin genes deleted singly, or in every possible combination of double deletions. Here, we exploit this adhesin mutant library to explore the role of adhesin proteins in C. albicans virulence. We perform a comprehensive, high-throughput screen of this library, using Caenorhabditis elegans as a simplified model host system, which identified mutants critical for virulence and significant genetic interactions. We perform follow-up analysis to assess the ability of high- and low-virulence strains to undergo cellular morphogenesis and form biofilms in vitro, as well as to colonize the C. elegans host. We further perform genetic interaction analysis to identify novel significant negative genetic interactions between adhesin mutants, whereby combinatorial perturbation of these genes significantly impairs virulence, more than expected based on virulence of the single mutant constituent strains. Together, this yields important new insight into the role of adhesins, singly and in combinations, in mediating diverse facets of virulence of this critical fungal pathogen.SummaryCandida albicans is a human fungal pathogen and cause of life-threatening systemic infections. Cell surface-associated adhesins play a central role in this pathogen’s ability to establish infection. Here, we provide a comprehensive analysis of adhesin factors, and their role in fungal virulence. Exploiting a high-throughput workflow, we screened an adhesin mutant library using C. elegans as a simple model host, and identified mutants and genetic interactions involved in virulence. We found that adhesin mutants are impaired in in vitro pathogenicity, irrespective of their virulence. Together, this work provides new insight into the role of adhesin factors in mediating fungal virulence.

scholarly journals Electrostatics of Tau Protein by Molecular Dynamics

Biomolecules ◽  
2019 ◽  
Vol 9 (3) ◽  
pp. 116 ◽  
Author(s):  
Tarsila Castro ◽  
Florentina-Daniela Munteanu ◽  
Artur Cavaco-Paulo
Keyword(s):  
Molecular Dynamics ◽  
3D Structure ◽  
Three Dimensional ◽  
Dynamics Simulation ◽  
Microtubule Assembly ◽  
Interaction Sites ◽  
Disordered Protein ◽  
Fluid Environment ◽  
Function Relationship ◽  
Insight Into

Tau is a microtubule-associated protein that promotes microtubule assembly and stability. This protein is implicated in several neurodegenerative diseases, including Alzheimer’s. To date, the three-dimensional (3D) structure of tau has not been fully solved, experimentally. Even the most recent information is sometimes controversial in regard to how this protein folds, interacts, and behaves. Predicting the tau structure and its profile sheds light on the knowledge about its properties and biological function, such as the binding to microtubules (MT) and, for instance, the effect on ionic conductivity. Our findings on the tau structure suggest a disordered protein, with discrete portions of well-defined secondary structure, mostly at the microtubule binding region. In addition, the first molecular dynamics simulation of full-length tau along with an MT section was performed, unveiling tau structure when associated with MT and interaction sites. Electrostatics and conductivity were also examined to understand how tau affects the ions in the intracellular fluid environment. Our results bring a new insight into tau and tubulin MT proteins, their characteristics, and the structure–function relationship.

scholarly journals Dynamics Studies of DNA with Non-canonical Structure Using NMR Spectroscopy

2020 ◽  
Vol 21 (8) ◽  
pp. 2673 ◽  
Author(s):  
Kwang-Im Oh ◽  
Jinwoo Kim ◽  
Chin-Ju Park ◽  
Joon-Hwa Lee
Keyword(s):  
Nmr Spectroscopy ◽  
Biological Function ◽  
Conformational Exchange ◽  
Biological Processes ◽  
Dynamic Characterization ◽  
Dynamic Features ◽  
Dna Structures ◽  
Left Handed ◽  
G Quadruplex ◽  
Insight Into

The non-canonical structures of nucleic acids are essential for their diverse functions during various biological processes. These non-canonical structures can undergo conformational exchange among multiple structural states. Data on their dynamics can illustrate conformational transitions that play important roles in folding, stability, and biological function. Here, we discuss several examples of the non-canonical structures of DNA focusing on their dynamic characterization by NMR spectroscopy: (1) G-quadruplex structures and their complexes with target proteins; (2) i-motif structures and their complexes with proteins; (3) triplex structures; (4) left-handed Z-DNAs and their complexes with various Z-DNA binding proteins. This review provides insight into how the dynamic features of non-canonical DNA structures contribute to essential biological processes.

scholarly journals Pyridoxal-5′-phosphate–dependent bifunctional enzyme catalyzed biosynthesis of indolizidine alkaloids in fungi

2019 ◽  
Vol 117 (2) ◽  
pp. 1174-1180 ◽  
Author(s):  
Guang Zhi Dai ◽  
Wen Bo Han ◽  
Ya Ning Mei ◽  
Kuang Xu ◽  
Rui Hua Jiao ◽  
...  
Keyword(s):  
Polyketide Synthase ◽  
Complex Structure ◽  
Genome Mining ◽  
Biosynthetic Gene Cluster ◽  
Major Facilitator Superfamily ◽  
Molecular Architecture ◽  
Widespread Occurrence ◽  
Indolizidine Alkaloids ◽  
Major Facilitator ◽  
Insight Into

Indolizidine alkaloids such as anticancer drugs vinblastine and vincristine are exceptionally attractive due to their widespread occurrence, prominent bioactivity, complex structure, and sophisticated involvement in the chemical defense for the producing organisms. However, the versatility of the indolizidine alkaloid biosynthesis remains incompletely addressed since the knowledge about such biosynthetic machineries is only limited to several representatives. Herein, we describe the biosynthetic gene cluster (BGC) for the biosynthesis of curvulamine, a skeletally unprecedented antibacterial indolizidine alkaloid from Curvularia sp. IFB-Z10. The molecular architecture of curvulamine results from the functional collaboration of a highly reducing polyketide synthase (CuaA), a pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (CuaB), an NADPH-dependent dehydrogenase (CuaC), and a FAD-dependent monooxygenase (CuaD), with its transportation and abundance regulated by a major facilitator superfamily permease (CuaE) and a Zn(II)Cys6 transcription factor (CuaF), respectively. In contrast to expectations, CuaB is bifunctional and capable of catalyzing the Claisen condensation to form a new C–C bond and the α-hydroxylation of the alanine moiety in exposure to dioxygen. Inspired and guided by the distinct function of CuaB, our genome mining effort discovers bipolamines A−I (bipolamine G is more antibacterial than curvulamine), which represent a collection of previously undescribed polyketide alkaloids from a silent BGC in Bipolaris maydis ATCC48331. The work provides insight into nature’s arsenal for the indolizidine-coined skeletal formation and adds evidence in support of the functional versatility of PLP-dependent enzymes in fungi.

scholarly journals The Role of the Fibronectin IGD Motif in Stimulating Fibroblast Migration

2007 ◽  
Vol 282 (49) ◽  
pp. 35530-35535 ◽  
Author(s):  
Christopher J. Millard ◽  
Ian R. Ellis ◽  
Andrew R. Pickford ◽  
Ana M. Schor ◽  
Seth L. Schor ◽  
...  
Keyword(s):  
Fibroblast Migration ◽  
Wide Range ◽  
Migration Stimulating Factor ◽  
Function Relationship ◽  
Relationship Of ◽  
Stimulating Factor ◽  
Insight Into ◽  
Stimulation Of

The motogenic activity of migration-stimulating factor, a truncated isoform of fibronectin (FN), has been attributed to the IGD motifs present in its FN type 1 modules. The structure-function relationship of various recombinant IGD-containing FN fragments is now investigated. Their structure is assessed by solution state NMR and their motogenic ability tested on fibroblasts. Even conservative mutations in the IGD motif are inactive or have severely reduced potency, while the structure remains essentially the same. A fragment with two IGD motifs is 100 times more active than a fragment with one and up to 106 times more than synthetic tetrapeptides. The wide range of potency in different contexts is discussed in terms of cryptic FN sites and cooperativity. These results give new insight into the stimulation of fibroblast migration by IGD motifs in FN.

Nonsuicidal Self-Injury and Its Relation to Suicidal Behavior

2014 ◽  
Author(s):  
Joseph C. Franklin ◽  
Matthew K. Nock
Keyword(s):  
Suicidal Behavior ◽  
Predictive Power ◽  
Suicide Attempts ◽  
Strong Association ◽  
Future Directions ◽  
Suicidal Intent ◽  
Self Injury ◽  
Basic Features ◽  
Insight Into ◽  
Nonsuicidal Self Injury

Nonsuicidal self-injury (NSSI) is the direct and intentional destruction of one’s own body tissue in the absence of suicidal intent. Although NSSI itself is explicitly nonsuicidal, nearly half of individuals who engage in NSSI also engage in suicidal behavior, and nearly all individuals who engage in suicidal behavior also engage in NSSI. Moreover, recent studies suggest that NSSI is one of the strongest known predictors of future suicide attempts, even exceeding the predictive power of prior suicide attempts in some instances. In this chapter we review the basic features and correlates of NSSI, evaluate the evidence for traditional models of NSSI, and discuss how an emerging model of NSSI may provide insight into the strong association between NSSI and suicidal behavior. We conclude by recommending how to evaluate when NSSI is a behavioral emergency and by noting the most crucial future directions for research on this topic.

scholarly journals Micro-FTIR and EPMA Characterisation of Charoite from Murun Massif (Russia)

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Maria Lacalamita
Keyword(s):  
Single Crystal ◽  
Complex Structure ◽  
Structural Complexity ◽  
Adsorbed Water ◽  
Bending Vibration ◽  
Structural Water ◽  
Stretching Vibration ◽  
Vibrational Features ◽  
Polytype Structure ◽  
Insight Into

Combined micro-Fourier transform infrared (micro-FTIR) and electron probe microanalyses (EPMA) were performed on a single crystal of charoite from Murun Massif (Russia) in order to get a deeper insight into the vibrational features of crystals with complex structure and chemistry. The micro-FTIR study of a single crystal of charoite was collected in the 6000–400 cm−1 at room temperature and after heating at 100°C. The structural complexity of this mineral is reflected by its infrared spectrum. The analysis revealed a prominent absorption in the OH stretching region as a consequence of band overlapping due to a combination of H2O and OH stretching vibrations. Several overtones of the O-H and Si-O stretching vibration bands were observed at about 4440 and 4080 cm−1 such as absorption possibly due to the organic matter at about 3000–2800 cm−1. No significant change due to the loss of adsorbed water was observed in the spectrum obtained after heating. The occurrence of well-resolved water bending vibration bands at about 1595 and 1667 cm−1 accounts for more than one structural water molecule as expected by charoite-90 polytype structure model from literature. The chemical composition of the studied crystal is close to the literature one.

scholarly journals Biphasic Force-Regulated Phosphorylation Site Exposure and Unligation of ERM Bound with PSGL-1: A Novel Insight into PSGL-1 Signaling via Steered Molecular Dynamics Simulations

2020 ◽  
Vol 21 (19) ◽  
pp. 7064
Author(s):  
Jingjing Feng ◽  
Yan Zhang ◽  
Quhuan Li ◽  
Ying Fang ◽  
Jianhua Wu
Keyword(s):  
Molecular Dynamics ◽  
Tensile Force ◽  
Complex Structure ◽  
Phosphorylation Site ◽  
Steered Molecular Dynamics ◽  
Structural Basis ◽  
Quasi Equilibrium ◽  
Dissociation Probability ◽  
Transition Mechanism ◽  
Insight Into

The PSGL-1-actin cytoskeleton linker proteins ezrin/radixin/moesin (ERM), an adaptor between P-selectin glycoprotein ligand-1 (PSGL-1) and spleen tyrosine kinase (Syk), is a key player in PSGL-1 signal, which mediates the adhesion and recruitment of leukocytes to the activated endothelial cells in flow. Binding of PSGL-1 to ERM initials intracellular signaling through inducing phosphorylation of Syk, but effects of tensile force on unligation and phosphorylation site exposure of ERM bound with PSGL-1 remains unclear. To answer this question, we performed a series of so-called “ramp-clamp” steered molecular dynamics (SMD) simulations on the radixin protein FERM domain of ERM bound with intracellular juxtamembrane PSGL-1 peptide. The results showed that, the rupture force of complex pulled with constant velocity was over 250 pN, which prevented the complex from breaking in front of pull-induced exposure of phosphorylation site on immunoreceptor tyrosine activation motif (ITAM)-like motif of ERM; the stretched complex structure under constant tensile forces <100 pN maintained on a stable quasi-equilibrium state, showing a high mechano-stabilization of the clamped complex; and, in consistent with the force-induced allostery at clamped stage, increasing tensile force (<50 pN) would decrease the complex dissociation probability but facilitate the phosphorylation site exposure, suggesting a force-enhanced biophysical connectivity of PSGL-1 signaling. These force-enhanced characters in both phosphorylation and unligation of ERM bound with PSGL-1 should be mediated by a catch-slip bond transition mechanism, in which four residue interactions on binding site were involved. This study might provide a novel insight into the transmembrane PSGL-1 signal, its biophysical connectivity and molecular structural basis for cellular immune responses in mechano-microenvironment, and showed a rational SMD-based computer strategy for predicting structure-function relation of protein under loads.

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