A transition state in pieces: major contributions of entropic effects to ligand binding by adenosine deaminase

Biochemistry ◽  
1992 ◽  
Vol 31 (32) ◽  
pp. 7356-7366 ◽  
Author(s):  
Warren M. Kati ◽  
Scott A. Acheson ◽  
Richard Wolfenden
Keyword(s):  
Ligand Binding ◽  
Transition State ◽  
Adenosine Deaminase ◽  
Entropic Effects

scholarly journals Kinetic Analysis of the Effect of Poliovirus Receptor on Viral Uncoating: the Receptor as a Catalyst

2001 ◽  
Vol 75 (11) ◽  
pp. 4984-4989 ◽  
Author(s):  
Simon K. Tsang ◽  
Brian M. McDermott ◽  
Vincent R. Racaniello ◽  
James M. Hogle
Keyword(s):  
Activation Energy ◽  
Transition State ◽  
Kinetic Analysis ◽  
Transition State Theory ◽  
State Theory ◽  
Viral Receptor ◽  
Poliovirus Receptor ◽  
Entropic Stabilization ◽  
Entropic Effects

ABSTRACT We examined the role of soluble poliovirus receptor on the transition of native poliovirus (160S or N particle) to an infectious intermediate (135S or A particle). The viral receptor behaves as a classic transition state theory catalyst, facilitating the N-to-A conversion by lowering the activation energy for the process by 50 kcal/mol. In contrast to earlier studies which demonstrated that capsid-binding drugs inhibit thermally mediated N-to-A conversion through entropic stabilization alone, capsid-binding drugs are shown to inhibit receptor-mediated N-to-A conversion through a combination of enthalpic and entropic effects.

scholarly journals The interplay of electrostatic fields and binding interactions determining catalytic-site reactivity in actinidin. A possible origin of differences in the behaviour of actinidin and papain

1989 ◽  
Vol 259 (2) ◽  
pp. 443-452 ◽  
Author(s):  
D Kowlessur ◽  
M O'Driscoll ◽  
C M Topham ◽  
W Templeton ◽  
E W Thomas ◽  
...  
Keyword(s):  
Hydrogen Bonding ◽  
Ligand Binding ◽  
Transition State ◽  
Rate Constant ◽  
Ph Dependence ◽  
Order Rate Constant ◽  
Catalytic Site ◽  
Binding Interactions ◽  
Electrostatic Fields ◽  
Transition State Geometry

1. The pH-dependence of the second-order rate constant (k) for the reaction of actinidin (EC 3.4.22.14) with 2-(N'-acetyl-L-phenylalanylamino)ethyl 2'-pyridyl disulphide was determined and the contributions to k of various hydronic states were evaluated. 2. The data were used to assess the consequences for transition-state geometry of providing P2/S2 hydrophobic contacts in addition to hydrogen-bonding opportunities in the S1-S2 intersubsite region. 3. The P2/S2 contacts (a) substantially improve enzyme-ligand binding, (b) greatly enhance the contribution to reactivity of the hydronic state bounded by pKa 3 (the pKa characteristic of the formation of catalytic-site-S-/-ImH+ state) and pKa 5 (a relatively minor contributor in reactions that lack the P2/S2 contacts), such that the major rate optimum occurs at pH 4 instead of at pH 2.8-2.9, and (c) reveal the kinetic influence of a pKa approx. 6.3 not hitherto observed in reactions of actinidin. 4. Possibilities for the interplay of electrostatic effects and binding interactions in both actinidin and papain (EC 3.4.22.2) are discussed.

The Chitopentaose Complex of a Mutant Hen Egg-White Lysozyme Displays No Distortion of the –1 Sugar Away from a 4C1 Chair Conformation

2009 ◽  
Vol 62 (6) ◽  
pp. 528 ◽  
Author(s):  
Gideon J. Davies ◽  
Stephen G. Withers ◽  
David J. Vocadlo
Keyword(s):  
Ligand Binding ◽  
Transition State ◽  
Chair Conformation ◽  
Egg White ◽  
Glycosidase Inhibitors ◽  
Hen Egg White Lysozyme ◽  
Egg White Lysozyme ◽  
Oxocarbenium Ion ◽  
Hen Egg White ◽  
Hen Egg

Glycosidase inhibitors frequently reflect either the charge or the ‘flattened’ shape of the oxocarbenium-ion like transition state. Much of the impetus for such inhibitory strategies derives from historical studies on ligand binding to hen egg white lysozyme (HEWL); not least those suggesting that product complexes of the enzyme showed distortion of the pyranosides in the –1 subsite. Ironically, while distortion is undoubtedly a defining feature of glycosidases, product complexes themselves are rarely distorted. Here we show that the chitopentaose product complex of a mutant E35Q HEWL, solved at 1.8 Å resolution, is bound with all sugars in 4C1 conformation.

scholarly journals Impact of protein–ligand solvation and desolvation on transition state thermodynamic properties of adenosine A2A ligand binding kinetics

2017 ◽  
Vol 5 (1) ◽  
Author(s):  
Giuseppe Deganutti ◽  
Andrei Zhukov ◽  
Francesca Deflorian ◽  
Stephanie Federico ◽  
Giampiero Spalluto ◽  
...  
Keyword(s):  
Thermodynamic Properties ◽  
Ligand Binding ◽  
Transition State ◽  
Binding Kinetics ◽  
Adenosine A2a

scholarly journals Membrane-mediated ligand unbinding of the PK-11195 ligand from TSPO

2020 ◽  
Author(s):  
Tom Dixon ◽  
Arzu Uyar ◽  
Shelagh Ferguson-Miller ◽  
Alex Dickson
Keyword(s):  
Ligand Binding ◽  
Transition State ◽  
Residence Time ◽  
Protein Interactions ◽  
Lipid Membrane ◽  
Binding Free Energy ◽  
First Passage Time ◽  
Passage Time ◽  
Translocator Protein ◽  
Trajectory Data

ABSTRACTThe translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is of longstanding medical interest as both a biomarker for neuroinjury and a potential drug target for neuroinflammation and other disorders. Recently it was shown that ligand residence time is a key factor determining steroidogenic efficacy of TSPO-binding compounds. This spurs interest in simulations of (un)binding pathways of TSPO ligands, which could reveal the molecular interactions governing ligand residence time. In this study, we use a weighted ensemble algorithm to determine the unbinding pathway for different poses of PK-11195, a TSPO ligand used in neuroimaging. In contrast with previous studies, our results show that PK-11195 does not dissociate directly into the solvent but instead dissociates via the lipid membrane by going between the transmembrane helices. We analyze this path ensemble in detail, constructing descriptors that can facilitate a general understanding of membrane-mediated ligand binding. We construct a Markov state model using additional straightforward simulations to determine pose stability and kinetics of ligand unbinding. Together we combine over 40 µs of trajectory data to form a coherent picture of the ligand binding landscape. We find that all poses are able to interconvert before unbinding, leading to single mean first passage time estimate for all starting poses which roughly agrees with the experimental quantity. The ligand binding transition state predicted by our combined model occurs when PK-11195 is already in the membrane and does not involve direct ligand-protein interactions. This has implications for the design of new long residence-time TSPO ligands.SIGNIFICANCEKinetics-oriented drug design is an emerging objective in drug discovery. However, while ligand binding affinity (or the binding free energy) is purely a function of the bound and unbound states, the binding kinetics depends on the nature of the paths by which the (un)binding occurs. This underscores the importance of approaches that can reveal information about the ensemble of (un)binding paths. Here we used advanced molecular dynamics approaches to study the unbinding of PK-11195 from TSPO and find it dissociates from the protein by dissolving into the membrane, and that the transition state occurs after the PK-11195 molecule has already separated from TSPO. These results motivate the design of future long-residence time TSPO ligands that destabilize the membrane-solvated transition state.

Hybrid QM/MM free energy evaluation of drug-resistant mutational effect on binding of an inhibitor Indinavir to HIV protease

2021 ◽  
Author(s):  
Masahiko Taguchi ◽  
Ryo Oyama ◽  
Masahiro Kaneso ◽  
Shigehiko Hayashi
Keyword(s):  
Drug Resistance ◽  
Free Energy ◽  
Ligand Binding ◽  
Transition State ◽  
Molecular Mechanism ◽  
Binding Affinity ◽  
Free Energy Calculations ◽  
Drug Resistant ◽  
Transition State Analog ◽  
Hiv 1

Human immunodeficiency virus 1 (HIV-1) protease is a homo-dimeric aspartic protease essential for replication of HIV. The HIV-1 protease is a target protein in drug discovery for antiretroviral therapy, and various inhibitor molecules of transition state analog were developed. However, serious drug-resistant mutants have emerged. For understanding molecular mechanism of the drug-resistance, accurate examination of the impacts of the mutations on ligand binding as well as enzymatic activity is necessary. Here, we present a molecular simulation study on the ligand binding of Indinavir, a potent transition state analog inhibitor, to the native protein and a V82T/I84V drug-resistant mutant of HIV-1 protease. We employed a hybrid ab initio quantum mechanical/molecular mechanical (QM/MM) free energy optimization technique which combines highly accurate QM description of the ligand molecule and its interaction with statistically ample conformational sampling of MM protein environment by long-time molecular dynamics simulations. Through free energy calculations of protonation states of catalytic groups at the binding pocket and of ligand binding affinity changes upon the mutations, we successfully reproduced the experimentally observed significant reduction of the binding affinity upon the drug-resistant mutations and elucidated the underlying molecular mechanism. The present study opens the way for understanding the molecular mechanism of drug-resistance through direct quantitative comparison of ligand binding and enzymatic reaction with the same accuracy.

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