scholarly journals Assessing the capability ofin silicomutation protocols for predicting the finite temperature conformation of amino acids

2018 ◽  
Vol 20 (40) ◽  
pp. 25901-25909 ◽  
Author(s):  
Rodrigo Ochoa ◽  
Miguel A. Soler ◽  
Alessandro Laio ◽  
Pilar Cossio
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Molecular Dynamics Simulations ◽  
Point Mutation ◽  
Finite Temperature ◽  
Single Point ◽  
Single Point Mutation ◽  
Equilibrium Configurations ◽  
Dynamics Simulations

Single-point mutation protocols based on backbone-dependent rotamer libraries show the best performance in predicting equilibrium configurations from molecular dynamics simulations.

scholarly journals Insight into a Novel p53 Single Point Mutation (G389E) by Molecular Dynamics Simulations

2010 ◽  
Vol 12 (1) ◽  
pp. 128-140 ◽  
Author(s):  
Davide Pirolli ◽  
Cristiana Carelli Alinovi ◽  
Ettore Capoluongo ◽  
Maria Antonia Satta ◽  
Paola Concolino ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Point Mutation ◽  
Single Point ◽  
Single Point Mutation ◽  
Dynamics Simulations ◽  
Insight Into

scholarly journals Mutation-Induced Conformational Changes and Energetics for Binding of FMN Ligand in Flavin Mononucleotide Riboswitch by Molecular Dynamics Simulations

2019 ◽  
Vol 92 (2) ◽  
pp. 241-247
Author(s):  
Padmaja D. Wakchaure ◽  
Bishwajit Ganguly
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Single Point ◽  
Regulatory Elements ◽  
Flavin Mononucleotide ◽  
Single Point Mutation ◽  
Valuable Insight ◽  
Natural Ligand ◽  
Dynamics Simulations

Riboswitches are the type of regulatory elements present in the untranslated region of mRNA and specifically bind to the natural ligand to regulate gene expression. This binding specificity can be affected by even single point mutation incorporated in the core of the riboswitch. In this work, we have examined the mutations at the binding site residue in Flavin Mononucleotide (FMN) riboswitch structure with 30ns molecular dynamics simulations. The interaction of ligand (FMN) with riboswitch has been characterized using root mean square deviation, hydrogen bonding analysis, and the calculated binding affinities. Mutation at A48G and G62U show the enhanced binding energy however, the mutation at A85G, are energetically unfavorable compared to the wild type. This work gives valuable insight into the structures and energetics of the mutated FMN riboswitch to design new hits for biological applications.

Finite Temperature Infrared Spectra from Polarizable Molecular Dynamics Simulations

2014 ◽  
Vol 10 (8) ◽  
pp. 3190-3199 ◽  
Author(s):  
David Semrouni ◽  
Ashwani Sharma ◽  
Jean-Pierre Dognon ◽  
Gilles Ohanessian ◽  
Carine Clavaguéra
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Infrared Spectra ◽  
Finite Temperature ◽  
Dynamics Simulations

Abstract 52: The Role of Kindlin-2 in Integrin Activation Depends on a Short C-Terminal Region

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Jamila Hirbawi ◽  
Kamila Bledzka ◽  
Yan Qing Ma ◽  
Jun Qin ◽  
Edward F Plow
Keyword(s):  
Amino Acids ◽  
Point Mutation ◽  
Single Point ◽  
Terminal Region ◽  
Membrane Receptors ◽  
Single Point Mutation ◽  
Loss Of Function ◽  
Integrin Activation ◽  
C Terminus

Integrins are heterodimeric cell membrane receptors that regulate cell adhesion, migration, and survival. The kindlins are known to be key regulators of integrin activation, the transition from a low affinity, default state to a high affinity state for ligand. This function depends on their binding, together with talin, to the cytoplasmic tails (CT) of the β subunit of integrins. Kindlins are FERM domain containing proteins, and it is its F3 (PTB) subdomain of the FERM that is the primary binding site for integrin β CT. At its very C-terminus, beyond the F3, is a short extension of 21 amino acids, K2 660-680, and we have focused on the role of this region in the co-activator function of kindlin-2 (K2). For this analysis, we performed PAC-1 (antibody to detect activated αIIbβ3 integrin) binding assays in CHO cells stably expressing integrin α IIb β 3 that were transiently transfected with talin head domain and K2 mutants. Expression levels of all proteins were verified to be similar by western blotting and FACS. Truncation of K2 at residue 660 essentially eliminated the co-activator function of K2. Deletion of smaller segments also reduced co-activator activity by 50% to 100%. Deletion of just the last two amino acids in the sequence, W 679 V 680 , resulted in a 50% reduction in co-activator activity and a single point mutation of Y 673 A also led to a 50% loss of function. A combination mutant consisting of the W 679 V 680 deletion and the Y 673 point mutation resulted in 100% loss of kindlin-2 co-activator activity. Pull-down experiments performed using GST tagged β 3 CT and CHO lysates transfected with GFP-kindlin-2 forms suggested that the C-terminal deletion did not disrupt binding to β 3 CT. This observation was corroborated by surface plasmon resonance studies in which the binding of full-length K2 and K2Δ666C (Δ666) was compared, and their K D values for immobilized β3 CT were found to be essentially the same. Overall, these data establish an important and unanticipated role of the carboxy-terminal region of kindlin-2 in its integrin co-activator function that is not dependent of its binding to integrin.

scholarly journals SLC6A14, a Pivotal Actor on Cancer Stage: When Function Meets Structure

2019 ◽  
Vol 24 (9) ◽  
pp. 928-938 ◽  
Author(s):  
Luca Palazzolo ◽  
Chiara Paravicini ◽  
Tommaso Laurenzi ◽  
Sara Adobati ◽  
Simona Saporiti ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acids ◽  
Amino Acid ◽  
Molecular Dynamics Simulations ◽  
Electrostatic Interactions ◽  
Amino Acid Residues ◽  
Dibasic Amino Acid ◽  
Novel Target ◽  
Function Relationship ◽  
Dynamics Simulations

SLC6A14 (ATB0,+) is a sodium- and chloride-dependent neutral and dibasic amino acid transporter that regulates the distribution of amino acids across cell membranes. The transporter is overexpressed in many human cancers characterized by an increased demand for amino acids; as such, it was recently acknowledged as a novel target for cancer therapy. The knowledge on the molecular mechanism of SLC6A14 transport is still limited, but some elegant studies on related transporters report the involvement of the 12 transmembrane α-helices in the transport mechanism, and describe structural rearrangements mediated by electrostatic interactions with some pivotal gating residues. In the present work, we constructed a SLC6A14 model in outward-facing conformation via homology modeling and used molecular dynamics simulations to predict amino acid residues critical for substrate recognition and translocation. We docked the proteinogenic amino acids and other known substrates in the SLC6A14 binding site to study both gating regions and the exposed residues involved in transport. Interestingly, some of these residues correspond to those previously identified in other LeuT-fold transporters; however, we could also identify a novel relevant residue with such function. For the first time, by combined approaches of molecular docking and molecular dynamics simulations, we highlight the potential role of these residues in neutral amino acid transport. This novel information unravels new aspects of the human SLC6A14 structure–function relationship and may have important outcomes for cancer treatment through the design of novel inhibitors of SLC6A14-mediated transport.

scholarly journals High-Level Chromosomally Mediated Tetracycline Resistance in Neisseria gonorrhoeae Results from a Point Mutation in the rpsJ Gene Encoding Ribosomal Protein S10 in Combination with the mtrR and penB Resistance Determinants

2005 ◽  
Vol 49 (10) ◽  
pp. 4327-4334 ◽  
Author(s):  
Mei Hu ◽  
Sobhan Nandi ◽  
Christopher Davies ◽  
Robert A. Nicholas
Keyword(s):  
Amino Acids ◽  
Neisseria Gonorrhoeae ◽  
Ribosomal Protein ◽  
Point Mutation ◽  
Single Point ◽  
Ribosomal Subunit ◽  
Tetracycline Resistance ◽  
Saturation Mutagenesis ◽  
Single Point Mutation ◽  
High Level

ABSTRACT Neisseria gonorrhoeae becomes resistant to tetracycline by two major mechanisms: expression of a plasmid-encoded TetM protein and mutations in endogenous genes (chromosomally mediated resistance). Early studies by Sparling and colleagues (P. F. Sparling F. A. J. Sarubbi, and E. Blackman, J. Bacteriol. 124:740-749, 1975) demonstrated that three genes were involved in high-level chromosomally mediated tetracycline resistance (MIC of tetracycline ≥ 2 μg/ml): ery-2 (now referred to as mtrR), penB, and tet-2. While the identities of the first two genes are known, the tet-2 gene has not been identified. We cloned the tet-2 gene, which confers tetracycline resistance, from tetracycline-resistant clinical isolate N. gonorrhoeae FA6140 and show that resistance is due to a single point mutation (Val-57 to Met) in the rpsJ gene (rpsJ1) encoding ribosomal protein S10. Moreover, the identical mutation was found in six distinct tetracycline-resistant clinical isolates in which the MIC of tetracycline was ≥2 μg/ml. Site-saturation mutagenesis of the codon for Val-57 identified two other amino acids (Leu and Gln) that conferred identical levels of resistance as the Met-57 mutation. The mutation maps to the vertex of a loop in S10 that is near the aminoacyl-tRNA site in the structure of the 30S ribosomal subunit from Thermus thermophilus, and the residue equivalent to Val-57 in T. thermophilus S10, Lys-55, is within 8 to 9 Å of bound tetracycline. These data suggest that large noncharged amino acids alter the rRNA structure near the tetracycline-binding site, leading to a lower affinity of the antibiotic.

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