Receptor dynamics in molecular recognition by Cryo-EM and molecular simulation

2020 ◽  
Vol 23 ◽  
Author(s):  
Yizhen Zhao ◽  
He Wang ◽  
Yongjian Zang ◽  
Xun Zhu ◽  
Shengli Zhang ◽  
...  
Keyword(s):  
Physiological State ◽  
Conformational Dynamics ◽  
Binding Affinities ◽  
Receptor Flexibility ◽  
Ensemble Docking ◽  
Receptor Structure ◽  
Receptor Dynamics ◽  
Selection Of ◽  
Low Energy Conformations

: The appropriate selection of initial receptor structure has been the "cornerstone" or foundation of successful structure-based virtual screening (SBVS), and plagued the structure-based design with a significantly practical problem to determine the major physiological states or important transition states of receptors (e.g. proteins with multiple low-energy conformations and ligand-dependent conformational dynamics). It is well known that current SBVS methods lack capacity to capture and characterize the intrinsic receptor flexibility with ideal cost-effectiveness. In recent years, cryoelectron microscopy (cryo-EM) has been routinely applied in the determination of biomolecular assemblies within physiological state. In this work, we review the roles of cryo-EM and ensemble docking methods to present the intrinsically dynamic behavior of biomacromolecules, as well as the ever-improving estimation of ligand binding affinities and receptor-ligand thermodynamics. Finally, we also provide an attitude for the further researches on the modeling receptor dynamics.

scholarly journals Conformational kinetics reveals affinities of protein conformational states

2015 ◽  
Vol 112 (30) ◽  
pp. 9352-9357 ◽  
Author(s):  
Kyle G. Daniels ◽  
Yang Suo ◽  
Terrence G. Oas
Keyword(s):  
Ligand Binding ◽  
Conformational Change ◽  
Conformational Changes ◽  
Rate Constants ◽  
Conformational Dynamics ◽  
Forward Rate ◽  
Binding Affinities ◽  
Conformational States ◽  
Kinetics Of

Most biological reactions rely on interplay between binding and changes in both macromolecular structure and dynamics. Practical understanding of this interplay requires detection of critical intermediates and determination of their binding and conformational characteristics. However, many of these species are only transiently present and they have often been overlooked in mechanistic studies of reactions that couple binding to conformational change. We monitored the kinetics of ligand-induced conformational changes in a small protein using six different ligands. We analyzed the kinetic data to simultaneously determine both binding affinities for the conformational states and the rate constants of conformational change. The approach we used is sufficiently robust to determine the affinities of three conformational states and detect even modest differences in the protein’s affinities for relatively similar ligands. Ligand binding favors higher-affinity conformational states by increasing forward conformational rate constants and/or decreasing reverse conformational rate constants. The amounts by which forward rate constants increase and reverse rate constants decrease are proportional to the ratio of affinities of the conformational states. We also show that both the affinity ratio and another parameter, which quantifies the changes in conformational rate constants upon ligand binding, are strong determinants of the mechanism (conformational selection and/or induced fit) of molecular recognition. Our results highlight the utility of analyzing the kinetics of conformational changes to determine affinities that cannot be determined from equilibrium experiments. Most importantly, they demonstrate an inextricable link between conformational dynamics and the binding affinities of conformational states.

DETERMINING THE DESALINATION UNIT COMPOSITION FOR COSTAL AREAS AND SMALL ISLANDS USE ANALYTIC HIERARCHY PROCESS

2017 ◽  
Vol 9 (1) ◽  
Author(s):  
Imam Setiadi ◽  
Dinda Rita K. Hartaja
Keyword(s):  
Analytic Hierarchy Process ◽  
Energy Demand ◽  
Pairwise Comparison ◽  
Small Islands ◽  
Ahp Method ◽  
Analytic Hierarchy ◽  
Comparison Research ◽  
Hierarchy Process ◽  
Selection Of

Selection of the appropriate composition desalination units can be done with a variety of method approaches, one of the method is the Analytic Hierarchy Process. In determining the desalination unit with AHP method to consider is setting a goal, an alternative criteria and pairwise comparison. Research for the determination of the exact composition of the desalination unit in order to achieve sustainable drinking water suppy in coastal areas and small islands has been conducted. The results of the study are as follows, the energy demand of 50.83%, operator costs of 26.64%, maintenance costs of 14.13% and chemical requirement 8.4%. For an alternative composition desalination unit of RO 10 m3 / day is the best alternative composition with value of 59.61%, the composition of the next alternative is RO 20 m3/ day of 30.40% and the last alternative of the desalination unit composition is RO 120 m3/ day of 09.99%.Key words : Desalination, Mukti Stage Flash Composition, AHP

Optimization of the selection of analysis methods for the determination of naturally occurring radionuclides

Kerntechnik ◽  
2008 ◽  
Vol 73 (3) ◽  
pp. 118-121
Author(s):  
T. Heinrich ◽  
L. Funke ◽  
M. Köhler ◽  
U.-K. Schkade ◽  
F. Ullrich ◽  
...  
Keyword(s):  
Naturally Occurring ◽  
Analysis Methods ◽  
Naturally Occurring Radionuclides ◽  
Selection Of

Determination of the minimum number of technological bases of a part

2020 ◽  
pp. 73-75
Author(s):  
B.M. Bazrov ◽  
T.M. Gaynutdinov
Keyword(s):  
Cost Price ◽  
Labor Input ◽  
Part Surface ◽  
Technological Base ◽  
Size Accuracy ◽  
Minimum Number ◽  
The Cost ◽  
Input Cost ◽  
Selection Of

The selection of technological bases is considered before the choice of the type of billet and the development of the route of the technological process. A technique is proposed for selecting the minimum number of sets of technological bases according to the criterion of equality in the cost price of manufacturing the part according to the principle of unity and combination of bases at this stage. Keywords: part, surface, coordinating size, accuracy, design and technological base, labor input, cost price. [email protected]

Is Hydraulics Over-Used or Under-Used in Storm Drainage?

1994 ◽  
Vol 29 (1-2) ◽  
pp. 53-61
Author(s):  
Ben Chie Yen
Keyword(s):  
Unsteady Flow ◽  
Computational Time ◽  
Time Step ◽  
Flow Routing ◽  
Kinematic Wave Equation ◽  
Storm Drainage ◽  
Saint Venant Equations ◽  
Unsteady Flow Routing ◽  
Selection Of

Urban drainage models utilize hydraulics of different levels. Developing or selecting a model appropriate to a particular project is not an easy task. Not knowing the hydraulic principles and numerical techniques used in an existing model, users often misuse and abuse the model. Hydraulically, the use of the Saint-Venant equations is not always necessary. In many cases the kinematic wave equation is inadequate because of the backwater effect, whereas in designing sewers, often Manning's formula is adequate. The flow travel time provides a guide in selecting the computational time step At, which in turn, together with flow unsteadiness, helps in the selection of steady or unsteady flow routing. Often the noninertia model is the appropriate model for unsteady flow routing, whereas delivery curves are very useful for stepwise steady nonuniform flow routing and for determination of channel capacity.

scholarly journals Recognition of hydrogen isotopomers by an open-cage fullerene

2013 ◽  
Vol 371 (1998) ◽  
pp. 20110629 ◽  
Author(s):  
Yasujiro Murata ◽  
Shih-Ching Chuang ◽  
Fumiyuki Tanabe ◽  
Michihisa Murata ◽  
Koichi Komatsu
Keyword(s):  
Equilibrium Constants ◽  
Equilibrium Mixture ◽  
Size Difference ◽  
Binding Affinities ◽  
Kinetic Isotope ◽  
Molecular Sizes ◽  
Lower Temperature ◽  
Kinetics Of ◽  
Pressure Hydrogen

We present our study on the recognition of hydrogen isotopes by an open-cage fullerene through determination of binding affinity of isotopes H 2 /HD/D 2 with the open-cage fullerene and comparison of their relative molecular sizes through kinetic-isotope-release experiments. We took advantage of isotope H 2 /D 2 exchange that generated an equilibrium mixture of H 2 /HD/D 2 in a stainless steel autoclave to conduct high-pressure hydrogen insertion into an open-cage fullerene. The equilibrium constants of three isotopes with the open-cage fullerene were determined at various pressures and temperatures. Our results show a higher equilibrium constant for HD into open-cage fullerene than the other two isotopomers, which is consistent with its dipolar nature. D 2 molecule generally binds stronger than H 2 because of its heavier mass; however, the affinity for H 2 becomes larger than D 2 at lower temperature, when size effect becomes dominant. We further investigated the kinetics of H 2 /HD/D 2 release from open-cage fullerene, proving their relative escaping rates. D 2 was found to be the smallest and H 2 the largest molecule. This notion has not only supported the observed inversion of relative binding affinities between H 2 and D 2 , but also demonstrated that comparison of size difference of single molecules through non-convalent kinetic-isotope effect was applicable.

Sign in / Sign up

Export Citation Format

Share Document