scholarly journals A Mechanism for the Rare Fluctuation that Powers Protein Conformational Change

2021 ◽  
Author(s):  
Shanshan Wu ◽  
Ao Ma
Keyword(s):  
Activation Barrier ◽  
Rare Event ◽  
Physical Nature ◽  
Structural Features ◽  
Isomerization Reaction ◽  
Activation Process ◽  
Space Condition ◽  
Reaction Coordinates ◽  
Gating Mechanism ◽  
Energy Activation

AbstractMost functional processes of biomolecules are rare events. Key to a rare event is the rare fluctuation that enables the energy activation process, which powers the system across the activation barrier. But the physical nature of this rare fluctuation and how it enables barrier crossing are unknown. With the help of a novel metric, the reaction capacity pC, that rigorously defines the beginning and parameterizes the progress of energy activation, the rare fluctuation was identified as a special phase-space condition that is necessary and sufficient for initiating systematic energy flow from the non-reaction coordinates into the reaction coordinates. The energy activation of a prototype biomolecular isomerization reaction is dominated by kinetic energy transferring into and accumulating in the reaction coordinates, administered by inertial forces alone. The two major reaction coordinates move in precise synergy, with one acting as a gating mechanism on the other. This mechanism is enabled by the structural features of biomolecules and may the cause of their unique functions that are not possible in small molecules.

Rare event simulation

2017 ◽  
Author(s):  
Michael P. Allen ◽  
Dominic J. Tildesley
Keyword(s):  
Rare Event ◽  
Path Sampling ◽  
Rapid Progress ◽  
Computationally Efficient ◽  
Transition Path ◽  
Transition Path Sampling ◽  
Event Simulation ◽  
Reaction Coordinates ◽  
Simulation Techniques ◽  
Transition Interface

The development of techniques to simulate infrequent events has been an area of rapid progress in recent years. In this chapter, we shall discuss some of the simulation techniques developed to study the dynamics of rare events. A basic summary of the statistical mechanics of barrier crossing is followed by a discussion of approaches based on the identification of reaction coordinates, and those which seek to avoid prior assumptions about the transition path. The demanding technique of transition path sampling is introduced and forward flux sampling and transition interface sampling are considered as rigorous but computationally efficient approaches.

scholarly journals Bioinformatics analysis of the structural and evolutionary characteristics for toll-like receptor 15

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e2079 ◽  
Author(s):  
Jinlan Wang ◽  
Zheng Zhang ◽  
Fen Chang ◽  
Deling Yin
Keyword(s):  
Convex Surface ◽  
Purifying Selection ◽  
Structural Features ◽  
Protein Docking ◽  
Activation Process ◽  
Docking Analysis ◽  
Unique Role ◽  
Evolutionarily Conserved ◽  
Interaction Interface ◽  
Tir Domains

Toll-like receptors (TLRs) play important role in the innate immune system. TLR15 is reported to have a unique role in defense against pathogens, but its structural and evolution characterizations are still poorly understood. In this study, we identified 57 completed TLR15 genes from avian and reptilian genomes. TLR15 clustered into an individual clade and was closely related to family 1 on the phylogenetic tree. Unlike the TLRs in family 1 with the broken asparagine ladders in the middle, TLR15 ectodomain had an intact asparagine ladder that is critical to maintain the overall shape of ectodomain. The conservation analysis found that TLR15 ectodomain had a highly evolutionarily conserved region on the convex surface of LRR11 module, which is probably involved in TLR15 activation process. Furthermore, the protein–protein docking analysis indicated that TLR15 TIR domains have the potential to form homodimers, the predicted interaction interface of TIR dimer was formed mainly by residues from the BB-loops andαC-helixes. Although TLR15 mainly underwent purifying selection, we detected 27 sites under positive selection for TLR15, 24 of which are located on its ectodomain. Our observations suggest the structural features of TLR15 which may be relevant to its function, but which requires further experimental validation.

scholarly journals Asymmetric Cyanation of Activated Olefins with Ethyl Cyanoformate Catalyzed by Ti(IV)-Catalyst: A Theoretical Study

Catalysts ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1079
Author(s):  
Zhishan Su ◽  
Changwei Hu ◽  
Nasir Shahzad ◽  
Chan Kyung Kim
Keyword(s):  
Transition State ◽  
Self Assembly ◽  
Theoretical Study ◽  
Activation Barrier ◽  
Cinchona Alkaloid ◽  
Activation Process ◽  
Construction Step ◽  
Dual Activation ◽  
Membered Transition State ◽  
Step Mechanism

The reaction mechanism and origin of asymmetric induction for conjugate addition of cyanide to the C=C bond of olefin were investigated at the B3LYP-D3(BJ)/6-31+G**//B3LYP-D3(BJ)/6-31G**(SMD, toluene) theoretical level. The release of HCN from the reaction of ethyl cyanoformate (CNCOOEt) and isopropanol (HOiPr) was catalyzed by cinchona alkaloid catalyst. The cyanation reaction of olefin proceeded through a two-step mechanism, in which the C-C bond construction was followed by H-transfer to generate a cyanide adduct. For non-catalytic reaction, the activation barrier for the rate-determining C-H bond construction step was 34.2 kcal mol−1, via a four-membered transition state. The self-assembly Ti(IV)-catalyst from tetraisopropyl titanate, (R)-3,3′-disubstituted biphenol, and cinchonidine accelerated the addition of cyanide to the C=C double bond by a dual activation process, in which titanium cation acted as a Lewis acid to activate the olefin and HNC was orientated by hydrogen bonding. The steric repulsion between the 9-phenanthryl at the 3,3′-position in the biphenol ligand and the Ph group in olefin raised the Pauli energy (ΔE≠Pauli) of reacting fragments at the re-face attack transition state, leading to the predominant R-product.

scholarly journals Unravelling novel synergies between organometallic and biological partners: a quantum mechanics/molecular mechanics study of an artificial metalloenzyme

2014 ◽  
Vol 11 (96) ◽  
pp. 20140090 ◽  
Author(s):  
Elisabeth Ortega-Carrasco ◽  
Agustí Lledós ◽  
Jean-Didier Maréchal
Keyword(s):  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Resting State ◽  
Structural Features ◽  
Activation Process ◽  
Biological Macromolecules ◽  
The Novel ◽  
Molecular Mechanics Calculations ◽  
Artificial Metalloenzymes ◽  
Artificial Metalloenzyme

In recent years, the design of artificial metalloenzymes obtained by the insertion of homogeneous catalysts into biological macromolecules has become a major field of research. These hybrids, and the corresponding X-ray structures of several of them, are offering opportunities to better understand the synergy between organometallic and biological subsystems. In this work, we investigate the resting state and activation process of a hybrid inspired by an oxidative haemoenzyme but presenting an unexpected reactivity and structural features. An extensive series of quantum mechanics/molecular mechanics calculations show that the resting state and the activation processes of the novel enzyme differ from naturally occurring haemoenzymes in terms of the electronic state of the metal, participation of the first coordination sphere of the metal and the dynamic process. This study presents novel insights into the sensitivity of the association between organometallic and biological partners and illustrates the molecular challenge that represents the design of efficient enzymes based on this strategy.

scholarly journals Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases

2020 ◽  
Author(s):  
Rory Crean ◽  
Michal Biler ◽  
Marc van der Kamp ◽  
Alvan C. Hengge ◽  
Shina Caroline Lynn Kamerlin
Keyword(s):  
Environmental Changes ◽  
Tyrosine Phosphatase ◽  
Conformational Dynamics ◽  
Rare Event ◽  
Protein Tyrosine Phosphatases ◽  
Structural Features ◽  
Tyrosine Phosphatases ◽  
Protein Tyrosine ◽  
Critical Residue ◽  
Loop Dynamics

<p>Protein tyrosine phosphatases (PTPs) play an important role in cellular signalling and have been implicated in human cancers, diabetes, and obesity. Despite shared catalytic mechanisms and transition states for the chemical steps of catalysis, catalytic rates within the PTP family vary over several orders of magnitude. These rate differences have been implied to arise from differing conformational dynamics of the closure of a protein loop, the WPD-loop, which carries a catalytically critical residue. The present work reports computational studies of the human protein tyrosine phosphatase 1B (PTP1B), and YopH from <i>Yersinia pestis</i>, for which NMR has demonstrated a link between both their respective rates of WPD-loop motion and catalysis rates, which differ by an order of magnitude. We have performed detailed structural analysis, both conventional and enhanced sampling simulations of their loop dynamics, as well as empirical valence bond simulations of the chemical step of catalysis. These analyses revealed the key residues and structural features responsible for these differences, as well as the residues and pathways that facilitate allosteric communication in these enzymes. Curiously, our wild-type YopH simulations also identify a catalytically incompetent hyper-open conformation of its WPD-loop, sampled as a rare event, previously only experimentally observed in YopH-based chimeras. The effect of differences within the WPD-loop and its neighbouring loops on the modulation of loop dynamics, as revealed in this work, may provide a facile means for the family of PTP enzymes to respond to environmental changes and regulate their catalytic activities. </p>

scholarly journals Structural Features and Ligand Selectivity for 10 Intermediates in the Activation Process of β2-Adrenergic Receptor

ACS Omega ◽  
2017 ◽  
Vol 2 (12) ◽  
pp. 8557-8567 ◽  
Author(s):  
Tao Liang ◽  
Yuan Yuan ◽  
Ran Wang ◽  
Yanzhi Guo ◽  
Menglong Li ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Structural Features ◽  
Activation Process ◽  
Ligand Selectivity ◽  
Β2 Adrenergic Receptor

scholarly journals Doubly-Charged Negative Ions as Novel Tunable Catalysts: Graphene and Fullerene Molecules Versus Atomic Metals

2020 ◽  
Vol 21 (18) ◽  
pp. 6714
Author(s):  
Kelvin Suggs ◽  
Alfred Z. Msezane
Keyword(s):  
Water Oxidation ◽  
Density Functional ◽  
Activation Barrier ◽  
Negative Ions ◽  
Negative Ion ◽  
Functional Theory ◽  
Molecular Anions ◽  
Sanitation Systems ◽  
Doubly Charged ◽  
Energy Activation

The fundamental mechanism underlying negative-ion catalysis involves bond-strength breaking in the transition state (TS). Doubly-charged atomic/molecular anions are proposed as novel dynamic tunable catalysts, as demonstrated in water oxidation into peroxide. Density Functional Theory TS calculations have found a tunable energy activation barrier reduction ranging from 0.030 eV to 2.070 eV, with Si2−, Pu2−, Pa2− and Sn2− being the best catalysts; the radioactive elements usher in new application opportunities. C602− significantly reduces the standard C60− TS energy barrier, while graphene increases it, behaving like cationic systems. According to their reaction barrier reduction efficiency, variation across charge states and systems, rank-ordered catalysts reveal their tunable and wide applications, ranging from water purification to biocompatible antiviral and antibacterial sanitation systems.

Recent structural and mechanistic insights into protein O-GalNAc glycosylation

2016 ◽  
Vol 44 (1) ◽  
pp. 61-67 ◽  
Author(s):  
Ramon Hurtado-Guerrero
Keyword(s):  
Rational Design ◽  
Structural Features ◽  
Ternary Complexes ◽  
Peptide Substrate ◽  
Post Translational Modification ◽  
Computational Simulations ◽  
Substrate Specificities ◽  
Reaction Coordinates ◽  
Complex Regulation

Protein O-GalNAcylation is an abundant post-translational modification and predicted to occur in over 80% of the proteins passing through the Golgi apparatus. This modification is driven by 20 polypeptide GaINAc (N-acetylgalactosamine)-transferases (GalNAc-Ts), which are unique in that they possess both catalytic and lectin domains. The peptide substrate specificities of GalNAc-Ts are still poorly defined and our understanding of the sequence and structural features that direct O-glycosylation of proteins is limited. Part of this may be attributed to the complex regulation by coordinated action of multiple GalNAc-T isoforms, and part of this may also be attributed to the two functional domains of GalNAc-Ts that both seems to be involved in directing the substrate specificities. Recent studies have resulted in 3D structures of GalNAc-Ts and determination of the reaction mechanism of this family of enzymes. Key advances include the trapping of binary/ternary complexes in combination with computational simulations and AFM/small-SAXS experiments, which have allowed for the dissection of the reaction coordinates and the mechanism by which the lectin domains modulate the glycosylation. These studies not only broaden our knowledge of the modes-of-action of this family of enzymes but also open up potential avenues for the rational design of effective and selective inhibitors of O-glycosylation.

scholarly journals A comparative study of n-hexane isomerization over solid acids catalysts: Sulfated and phosphated zirconia

2012 ◽  
Vol 18 (2) ◽  
pp. 209-220 ◽  
Author(s):  
N. Stojkovic ◽  
M. Vasic ◽  
M. Marinkovic ◽  
M. Randjelovic ◽  
M. Purenovic ◽  
...  
Keyword(s):  
Chemical Properties ◽  
Active Phase ◽  
Structural Features ◽  
Site Formation ◽  
Isomerization Reaction ◽  
Total Acidity ◽  
Sulfated Zirconia Catalyst ◽  
Different Temperatures ◽  
Lower Temperature ◽  
Solid Acids Catalysts

Two series of zirconia based catalysts promoted with either sulfates or phosphates were prepared, calcined at different temperatures (600 and 700?C) and evaluated for the n-hexane isomerization reaction. The catalysts with different concentrations of sulfates or phosphates (4 or 10 wt. %) were characterized by BET, XRD, SEM methods, and total acidity was evaluated by using the Hammett indicators. Their final catalytic performances were correlated with their physical-chemical properties (surface, structural, textural and morphological). It was found that sulfated zirconia catalyst calcined at lower temperature showed the highest initial activity of all tested catalysts as the result of favorable total acidity, mesopore texture and structural properties. Somewhat lower activity of the sulfated catalyst calcined at higher temperature is related to the content of acid groups partially removed during thermal treatment, thus, lower total acidity, and also to less favorable textural and structural features. Negligible activity of phosphated zirconia catalysts is connected with low total acidity despite the positive status of particular property showing the complexity of the active phase/site formation in the catalyst.

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