Directional Selection Precedes Conformational Selection in Ubiquitin-UIM Binding

2013 ◽  
Vol 52 (13) ◽  
pp. 3709-3711 ◽  
Author(s):  
Dong Long ◽  
Rafael Brüschweiler
Keyword(s):  
Directional Selection ◽  
Conformational Selection

Directional Selection Precedes Conformational Selection in Ubiquitin-UIM Binding

2013 ◽  
Vol 125 (13) ◽  
pp. 3797-3799
Author(s):  
Dong Long ◽  
Rafael Brüschweiler
Keyword(s):  
Directional Selection ◽  
Conformational Selection

Association/dissociation Mechanisms of Intrinsically Disordered Region of Protein Beyond Conformational Selection and Induced Fit

2019 ◽  
Author(s):  
Duy Phuoc Tran ◽  
Akio Kitao
Keyword(s):  
Free Energy ◽  
Transcriptional Activation ◽  
Binding Free Energy ◽  
Energy Structure ◽  
Induced Fit ◽  
Hydrogen Bond Formation ◽  
Conformational Selection ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Region ◽  
Dissociation Mechanisms

<p>We investigate association and dissociation mechanisms of a typical intrinsically disordered region (IDR), transcriptional activation subdomain of tumor repressor protein p53 (TAD-p53) with murine double-minute clone 2 protein (MDM2). Using the combination of cycles of association and dissociation parallel cascade molecular dynamics, multiple standard MD, and Markov state model, we are successful in obtaining the lowest free energy structure of MDM2/TAD-p53 complex as the structure very close to that in crystal without prior knowledge. This method also reproduces the experimentally measured standard binding free energy, and association and dissociation rate constants solely with the accumulated MD simulation cost of 11.675 μs, in spite of the fact that actual dissociation occurs in the order of a second. Although there exist a few complex intermediates with similar free energies, TAD-p53 first binds MDM2 as the second lowest free energy intermediate dominantly (> 90% in flux), taking a form similar to one of the intermediate structures in its monomeric state. The mechanism of this step has a feature of conformational selection. In the second step, dehydration of the interface, formation of π-π stackings of the side-chains, and main-chain relaxation/hydrogen bond formation to complete α-helix take place, showing features of induced fit. In addition, dehydration (dewetting) is a key process for the final relaxation around the complex interface. These results demonstrate a more fine-grained view of the IDR association/dissociation beyond classical views of protein conformational change upon binding.</p>

Schistosomal Sulfotransferase Interaction with Oxamniquine Involves Hybrid Mechanism of Induced-fit and Conformational Selection

2020 ◽  
Vol 16 (4) ◽  
pp. 451-459 ◽  
Author(s):  
Fortunatus C. Ezebuo ◽  
Ikemefuna C. Uzochukwu
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Binding Energy ◽  
Binding Site ◽  
Conformational Dynamics ◽  
Side Chain ◽  
Amino Acid Residues ◽  
Conformational Selection ◽  
Hybrid Mechanism ◽  
Dynamics Simulations

Background: Sulfotransferase family comprises key enzymes involved in drug metabolism. Oxamniquine is a pro-drug converted into its active form by schistosomal sulfotransferase. The conformational dynamics of side-chain amino acid residues at the binding site of schistosomal sulfotransferase towards activation of oxamniquine has not received attention. Objective: The study investigated the conformational dynamics of binding site residues in free and oxamniquine bound schistosomal sulfotransferase systems and their contribution to the mechanism of oxamniquine activation by schistosomal sulfotransferase using molecular dynamics simulations and binding energy calculations. Methods: Schistosomal sulfotransferase was obtained from Protein Data Bank and both the free and oxamniquine bound forms were subjected to molecular dynamics simulations using GROMACS-4.5.5 after modeling it’s missing amino acid residues with SWISS-MODEL. Amino acid residues at its binding site for oxamniquine was determined and used for Principal Component Analysis and calculations of side-chain dihedrals. In addition, binding energy of the oxamniquine bound system was calculated using g_MMPBSA. Results: The results showed that binding site amino acid residues in free and oxamniquine bound sulfotransferase sampled different conformational space involving several rotameric states. Importantly, Phe45, Ile145 and Leu241 generated newly induced conformations, whereas Phe41 exhibited shift in equilibrium of its conformational distribution. In addition, the result showed binding energy of -130.091 ± 8.800 KJ/mol and Phe45 contributed -9.8576 KJ/mol. Conclusion: The results showed that schistosomal sulfotransferase binds oxamniquine by relying on hybrid mechanism of induced fit and conformational selection models. The findings offer new insight into sulfotransferase engineering and design of new drugs that target sulfotransferase.

scholarly journals Directional Selection and the Site-Frequency Spectrum

Genetics ◽  
2001 ◽  
Vol 159 (4) ◽  
pp. 1779-1788 ◽  
Author(s):  
Carlos D Bustamante ◽  
John Wakeley ◽  
Stanley Sawyer ◽  
Daniel L Hartl
Keyword(s):  
Maximum Likelihood ◽  
High Power ◽  
Negative Selection ◽  
Likelihood Estimation ◽  
Directional Selection ◽  
Likelihood Ratio Tests ◽  
Maximum Likelihood Estimates ◽  
Likelihood Methods ◽  
Ancestral States ◽  
Asymptotic Variances

Abstract In this article we explore statistical properties of the maximum-likelihood estimates (MLEs) of the selection and mutation parameters in a Poisson random field population genetics model of directional selection at DNA sites. We derive the asymptotic variances and covariance of the MLEs and explore the power of the likelihood ratio tests (LRT) of neutrality for varying levels of mutation and selection as well as the robustness of the LRT to deviations from the assumption of free recombination among sites. We also discuss the coverage of confidence intervals on the basis of two standard-likelihood methods. We find that the LRT has high power to detect deviations from neutrality and that the maximum-likelihood estimation performs very well when the ancestral states of all mutations in the sample are known. When the ancestral states are not known, the test has high power to detect deviations from neutrality for negative selection but not for positive selection. We also find that the LRT is not robust to deviations from the assumption of independence among sites.

From Selection to Instruction and Back — Competing Conformational Selection and Induced Fit Pathways in Abiotic Hosts

2021 ◽  
Author(s):  
Jovica D Badjic ◽  
Radoslav Z Pavlović ◽  
Remy F Lalisse ◽  
Alexandar L Hansen ◽  
Christopher A Waudby ◽  
...  
Keyword(s):  
Induced Fit ◽  
Conformational Selection

scholarly journals A Quantitative Genetic Analysis of Male Sexual Traits Distinguishing the Sibling Species Drosophila simulans and D. sechellia

Genetics ◽  
1999 ◽  
Vol 153 (4) ◽  
pp. 1683-1699 ◽  
Author(s):  
Stuart J Macdonald ◽  
David B Goldstein
Keyword(s):  
Genetic Analysis ◽  
Sibling Species ◽  
Reproductive Traits ◽  
Drosophila Simulans ◽  
Directional Selection ◽  
Posterior Lobe ◽  
Sex Comb ◽  
Tooth Number ◽  
Comb Tooth ◽  
Shape And Size

Abstract A quantitative trait locus (QTL) genetic analysis of morphological and reproductive traits distinguishing the sibling species Drosophila simulans and D. sechellia was carried out in a backcross design, using 38 markers with an average spacing of 8.4 cM. The direction of QTL effects for the size of the posterior lobe was consistent across the identified QTL, indicating directional selection for this trait. Directional selection also appears to have acted on testis length, indicating that sexual selection may have influenced many reproductive traits, although other forms of directional selection cannot be ruled out. Sex comb tooth number exhibited high levels of variation both within and among isofemale lines and showed no evidence for directional selection and, therefore, may not have been involved in the early speciation process. A database search for genes associated with significant QTL revealed a set of candidate loci for posterior lobe shape and size, sex comb tooth number, testis length, tibia length, and hybrid male fertility. In particular, decapentaplegic (dpp), a gene known to influence the genital arch, was found to be associated with the largest LOD peak for posterior lobe shape and size.

scholarly journals Detecting a Local Signature of Genetic Hitchhiking Along a Recombining Chromosome

Genetics ◽  
2002 ◽  
Vol 160 (2) ◽  
pp. 765-777 ◽  
Author(s):  
Yuseob Kim ◽  
Wolfgang Stephan
Keyword(s):  
Genetic Variation ◽  
Dna Polymorphism ◽  
Nucleotide Diversity ◽  
Sequence Data ◽  
Directional Selection ◽  
Genetic Hitchhiking ◽  
Dna Sequence Data ◽  
Local Reduction ◽  
Polymorphism Data ◽  
Ancestral Recombination Graphs

Abstract The theory of genetic hitchhiking predicts that the level of genetic variation is greatly reduced at the site of strong directional selection and increases as the recombinational distance from the site of selection increases. This characteristic pattern can be used to detect recent directional selection on the basis of DNA polymorphism data. However, the large variance of nucleotide diversity in samples of moderate size imposes difficulties in detecting such patterns. We investigated the patterns of genetic variation along a recombining chromosome by constructing ancestral recombination graphs that are modified to incorporate the effect of genetic hitchhiking. A statistical method is proposed to test the significance of a local reduction of variation and a skew of the frequency spectrum caused by a hitchhiking event. This method also allows us to estimate the strength and the location of directional selection from DNA sequence data.

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