scholarly journals Molecular dynamics derived life times of active substrate binding poses explainKMof laccase mutants

RSC Advances ◽  
2018 ◽  
Vol 8 (64) ◽  
pp. 36915-36926 ◽  
Author(s):  
Rukmankesh Mehra ◽  
Anne S. Meyer ◽  
Kasper P. Kepp
Keyword(s):  
Molecular Dynamics ◽  
Substrate Binding ◽  
Active Substrate ◽  
Substrate Affinities

Molecular dynamics derived life times of reactive poses and MMGBSA substrate affinities explain trends in experimentalKMfor laccases.

scholarly journals Multiple proteolytic events in caspase-6 self-activation impact conformations of discrete structural regions

2017 ◽  
Vol 114 (38) ◽  
pp. E7977-E7986 ◽  
Author(s):  
Kevin B. Dagbay ◽  
Jeanne A. Hardy
Keyword(s):  
Substrate Binding ◽  
Complete Removal ◽  
Bound State ◽  
Solvent Exposure ◽  
Strategic Design ◽  
Intrinsically Disordered ◽  
Parkinson’S Diseases ◽  
Active Substrate ◽  
Hydrogen Deuterium ◽  
Caspase 6

Caspase-6 is critical to the neurodegenerative pathways of Alzheimer’s, Huntington’s, and Parkinson’s diseases and has been identified as a potential molecular target for treatment of neurodegeneration. Thus, understanding the global and regional changes in dynamics and conformation provides insights into the unique properties of caspase-6 that may contribute to achieving control of its function. In this work, hydrogen/deuterium exchange MS (H/DX–MS) was used to map the local changes in the conformational flexibility of procaspase-6 at the discrete states that reflect the series of cleavage events that ultimately lead to the fully active, substrate-bound state. Intramolecular self-cleavage at Asp-193 evoked higher solvent exposure in the regions of the substrate-binding loops L1, L3, and L4 and in the 130s region, the intersubunit linker region, the 26–32 region as well as in the stabilized loop 2. Additional removal of the linker allowed caspase-6 to gain more flexibility in the 130s region and in the L2 region converting caspase-6 to a competent substrate-binding state. The prodomain region was found to be intrinsically disordered independent of the activation state of caspase-6; however, its complete removal resulted in the protection of the adjacent 26–32 region, suggesting that this region may play a regulatory role. The molecular details of caspase-6 dynamics in solution provide a comprehensive scaffold for strategic design of therapeutic approaches for neurodegenerative disorders.

A molecular dynamics study of the complete binding process of meropenem to New Delhi metallo-β-lactamase 1

2018 ◽  
Vol 20 (9) ◽  
pp. 6409-6420 ◽  
Author(s):  
Juan Duan ◽  
Chuncai Hu ◽  
Jiafan Guo ◽  
Lianxian Guo ◽  
Jia Sun ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Substrate Binding ◽  
New Delhi ◽  
Binding Process ◽  
Dynamics Simulations

We have investigated the substrate-binding pathways of NDM-1 via unbiased molecular dynamics simulations and metadynamics.

scholarly journals Molecular dynamics and structure function analysis show that substrate binding and specificity are major forces in the functional diversification of Eqolisins

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Nicolás Stocchi ◽  
María Victoria Revuelta ◽  
Priscila Ailín Lanza Castronuovo ◽  
D. Mariano A. Vera ◽  
Arjen ten Have
Keyword(s):  
Molecular Dynamics ◽  
Structure Function ◽  
Function Analysis ◽  
Substrate Binding ◽  
Functional Diversification

Molecular dynamics insights into the structure, function, and substrate binding mechanism of mucin desulfating sulfatase of gut microbe Bacteroides fragilis

2018 ◽  
Vol 119 (4) ◽  
pp. 3618-3631 ◽  
Author(s):  
Ardhendu Bhusan Praharaj ◽  
Budheswar Dehury ◽  
Namita Mahapatra ◽  
Shantanu Kumar Kar ◽  
Santosh Kumar Behera
Keyword(s):  
Molecular Dynamics ◽  
Structure Function ◽  
Substrate Binding ◽  
Bacteroides Fragilis ◽  
Binding Mechanism ◽  
Gut Microbe

scholarly journals Substrate binding and specificity appear as major forces in the functional diversification of eqolisins

2017 ◽  
Author(s):  
María Victoria Revuelta ◽  
Nicolas Stocchi ◽  
Priscila Ailín Lanza Castronuovo ◽  
Mariano Vera ◽  
Arjen ten Have
Keyword(s):  
Molecular Dynamics ◽  
Substrate Specificity ◽  
Double Mutant ◽  
Substrate Binding ◽  
Salt Bridge ◽  
Functional Diversification ◽  
Specificity Determining Positions ◽  
The Subject ◽  
Bacteria And Fungi ◽  
Dynamics Simulations

AbstractBackgroundEqolisins are rare acid proteases found in archaea, bacteria and fungi. Certain fungi secrete acids as part of their lifestyle and interestingly these also have many eqolisin paralogs, up to nine paralogs have been recorded. This suggests functional redundancy and diversification, which was the subject of the research we performed and describe here.ResultsWe identified eqolisin homologs by means of iterative HMMER analysis of the NR database. The identified sequences were scrutinized for which we defined novel hallmarks, identified by molecular dynamics simulations of mutants of highly conserved positions, using the structure of an eqolisin that was crystallized in the presence of a transition state inhibitor. Four conserved glycines were shown to be required for functionality. A substitution of W67F is shown to be accompanied by the L105W substitution. Molecular dynamics shows that the W67 binds to the substrate via a π-π stacking and a salt bridge, the latter being stronger in a virtual W67F/L105W double mutant of the resolved structure of Scytalido-carboxyl peptidase-B (PDB ID: 2IFW)). Additional likely fatal mutants are discussed.Upon sequence scrutiny we obtained a set of 233 sequences that in all likelihood lack false positives. This was used to reconstruct a Bayesian phylogenetic tree. We identified 14 putative specificity determining positions (SDPs) of which four are explained by mere structural explanations and nine seem to correspond to functional diversification related wit substrate binding ans specificity. A first sub-network of SDPs is related to substrate specificity whereas the second sub-network seems to affect the dynamics of three loops that are involved in substrate binding.HighlightsEqolisins are acid proteases found in prokaryotes and fungi only.The recently co-evolved W67F-L105W substitutions promote substrate bindingTwo Specificity Determining Networks, SDN1 and 2, were identifiedSDN1 has four Specificity Determining Positions involved in substrate specificitySDN2 has five Specificity Determining Positions involved in loop-substrate dynamics

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