scholarly journals pH-dependent interactions of Apolipophorin-III with a lipid disk

2020 ◽  
pp. 2042004
Author(s):  
Yunhui Peng ◽  
Rudolfs Kelle ◽  
Chandler Little ◽  
Ekaterina Michonova ◽  
Kostantin G. Kornev ◽  
...  
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Binding Free Energy ◽  
Ph Dependence ◽  
Binding Mode ◽  
Ph Optimum ◽  
Apolipophorin Iii ◽  
Head Groups ◽  
Molecular Shuttles ◽  
Ph Range

Apolipophorin-III (ApoLp-III) is required for stabilization of molecular shuttles of lipid fuels in insects and is found to contribute to the insect immune reaction. Rearrangement of its five [Formula: see text]-helices enables ApoLp-III to reversibly associate with lipids. We investigate computationally the conformational changes of ApoLp-III and the pH-dependence of the binding free energy of ApoLp-III association with a lipid disk. A dominant binding mode along with several minor, low population, modes of the ApoLp-III binding to a lipid disk was identified. The pH-dependence of the binding energy for ApoLp-III with the lipid disk is predicted to be significant, with the pH-optimum at pH[Formula: see text]. The calculations suggest that there are no direct interactions between the lipid head groups and titratable residues of ApoLp-III. In the physiological pH range from 6.0 to 9.0, the binding free energy of ApoLp-III with the lipid disk decreases significantly with respect to its optimal value at pH 8.0 (at pH[Formula: see text], it is 1.02[Formula: see text]kcal/mol and at pH[Formula: see text] it is 0.23[Formula: see text]kcal/mol less favorable than at the optimal pH[Formula: see text]), indicating that the pH is an important regulator of ApoLp-III lipid disk association.

scholarly journals pH-Dependent Interactions of Apolipophorin-III with a Lipid Disk

2020 ◽  
pp. 1-12
Author(s):  
Yunhui Peng ◽  
Rudolfs Kelle ◽  
Chandler Little ◽  
Ekaterina Michonova ◽  
Kostantin G. Kornev ◽  
...  
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Binding Free Energy ◽  
Ph Dependence ◽  
Binding Mode ◽  
Ph Optimum ◽  
Apolipophorin Iii ◽  
Head Groups ◽  
Molecular Shuttles ◽  
Ph Range

Apolipophorin-III (ApoLp-III) is required for stabilization of molecular shuttles of lipid fuels in insects and is found to contribute to the insect immune reaction. Rearrangement of its five [Formula: see text]-helices enables ApoLp-III to reversibly associate with lipids. We investigate computationally the conformational changes of ApoLp-III and the pH-dependence of the binding free energy of ApoLp-III association with a lipid disk. A dominant binding mode along with several minor, low population, modes of the ApoLp-III binding to a lipid disk was identified. The pH-dependence of the binding energy for ApoLp-III with the lipid disk is predicted to be significant, with the pH-optimum at pH[Formula: see text]. The calculations suggest that there are no direct interactions between the lipid head groups and titratable residues of ApoLp-III. In the physiological pH range from 6.0 to 9.0, the binding free energy of ApoLp-III with the lipid disk decreases significantly with respect to its optimal value at pH 8.0 (at pH[Formula: see text], it is 1.02[Formula: see text]kcal/mol and at pH[Formula: see text] it is 0.23[Formula: see text]kcal/mol less favorable than at the optimal pH[Formula: see text]), indicating that the pH is an important regulator of ApoLp-III lipid disk association.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

scholarly journals Interaction of Coumarin Phytoestrogens with ERα and ERβ: A Molecular Dynamics Simulation Study

Molecules ◽  
2020 ◽  
Vol 25 (5) ◽  
pp. 1165 ◽  
Author(s):  
Ting Wang ◽  
Yunfei Wang ◽  
Xuming Zhuang ◽  
Feng Luan ◽  
Chunyan Zhao ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Binding Free Energy ◽  
Human Life ◽  
Simulation Method ◽  
Binding Mode ◽  
Dynamics Simulation ◽  
Molecular Dynamics Methods ◽  
17Β Estradiol ◽  
The Stability

Coumarin phytoestrogens, as one of the important classes of phytoestrogens, have been proved to play an important role in various fields of human life. In this study, molecular simulation method including molecular docking and molecular dynamics methods were performed to explore the various effects between four classical coumarin phytoestrogens (coumestrol, 4-methoxycoumestrol, psoralen and isopsoralen), and estrogen receptors (ERα, ERβ), respectively. The calculated results not only proved that the four coumarin phytoestrogens have weaker affinity than 17β-estradiol to both ERα, and ERβ, but also pointed out that the selective affinity for ERβ is greater than ERα. In addition, the binding mode indicated that the formation of hydrogen bond and hydrophobic interaction have an important effect on the stability of the complexes. Further, the calculation and decomposition of binding free energy explored the main contribution interactions to the total free energy.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

scholarly journals The HSP90 binding mode of a radicicol-like E-oxime determined by docking, binding free energy estimations, and NMR 15N chemical shifts

2009 ◽  
Vol 143 (3) ◽  
pp. 111-123 ◽  
Author(s):  
Martin Spichty ◽  
Antoine Taly ◽  
Franz Hagn ◽  
Horst Kessler ◽  
Sofia Barluenga ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Chemical Shifts ◽  
Binding Mode

scholarly journals The ‘natural’ hybrid haemoglobin from mule. Interrelationships with its parent haemoglobins from horse and donkey

1992 ◽  
Vol 282 (2) ◽  
pp. 595-599 ◽  
Author(s):  
S G Condò ◽  
M Coletta ◽  
R Cicchetti ◽  
G Argentin ◽  
P Guerrieri ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Binding Mode ◽  
Natural Hybrid ◽  
Binding Properties ◽  
Inositol Hexakisphosphate ◽  
Physiological Conditions ◽  
General Terms ◽  
O2 Binding

The equilibrium O2-binding properties of the hybrid haemoglobin (Hb) present in vivo in erythrocytes from mule and of its parent Hbs from horse and donkey were compared with special reference to the effect of heterotropic ligands such as Cl-, D-glycerate 2,3-bisphosphate (DPG) and inositol hexakisphosphate. All these Hbs display a decreased effect by polyphosphates, confirming that what has been observed for horse Hb [Giardina, Brix, Clementi, Scatena, Nicoletti, Cicchetti, Argentin & Condò (1990) Biochem. J. 266, 897-900] is common to other equine species, at least from a qualitative standpoint. However, different quantitative aspects can be detected, which can be accounted for by a different role for the two types of chain in characterizing the binding free energy for the various heterotropic effectors. In particular, it is shown that the binding mode of DPG and inositol hexakisphosphate displays different features since long-range effects can be observed clearly for inositol hexakisphosphate but not for DPG. In general terms, in spite of a different intrinsic O2 affinity, the modulation of functional properties by third ligands leads these Hbs to behave, under physiological conditions, similarly to human HbA. It might represent an interesting example of how different species with similar functional needs find different ways to produce a similar functional behaviour.

scholarly journals An Improved Free Energy Perturbation FEP+ Sampling Protocol for Flexible Ligand-Binding Domains

2019 ◽  
Author(s):  
Filip Fratev ◽  
suman sirimulla
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Conformational Changes ◽  
Structural Changes ◽  
Binding Mode ◽  
Sampling Time ◽  
Free Energy Perturbation ◽  
Sampling Protocol ◽  
Sampling Schemes ◽  
Energy Perturbation

Recent improvements to free energy perturbation (FEP) calculations, especiallyFEP+, established their utility for pharmaceutical lead optimization. However, to dateFEP has typically been helpful only when (1) high-quality X-ray data is available and(2) the target protein does not undergo significant conformational changes. Also, alack of systematic studies on determining an adequate sampling time is often one ofthe primary limitations of FEP calculations. Herein, we propose a modified versionof the FEP/REST (i.e., replica exchange with solute tempering) sampling protocol,based on systematic studies on several targets by probing a large number of permutations with different sampling schemes. Improved FEP+ binding affinity predictions for regular flexible-loop (F-loop) motions and considerable structural changes can be obtained by extending the pre-REST sampling time from 0.24 ns to 5 ns/λand 2×10 ns/λ, respectively. We obtained much more precise ∆∆G calculations of the individual perturbations, including the sign of the transformations and less error. We extended the REST simulations from 5 ns to 8 ns to achieve reasonable free energy convergence.Implementing REST to the entire ligand as opposed to solely the perturbed region, and also some important flexible protein residues (pREST region) in ligand binding domain (LBD) , also considerably improved the FEP+ results in most of the studied cases. Preliminary molecular dynamics (MD) runs were useful for establishing the correct binding mode of the compounds and thus precise alignment for FEP+.<br>

scholarly journals Nelfinavir was predicted to be a potential inhibitor of 2019-nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation

2020 ◽  
Author(s):  
Zhijian Xu ◽  
Cheng Peng ◽  
Yulong Shi ◽  
Zhengdan Zhu ◽  
Kaijie Mu ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Homology Modelling ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Integrative Approach ◽  
Energy Calculation ◽  
Potential Inhibitor ◽  
Small Molecule Drugs ◽  
Main Protease

Abstract2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov Mpro is a potential drug target to combat the virus. We built homology models based on SARS Mpro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known Mpro ligands, 4 drugs were selected for binding free energy calculations. Both MM/GBSA and SIE methods voted for nelfinavir, with the binding free energy of −24.69±0.52 kcal/mol and −9.42±0.04 kcal/mol, respectively. Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov Mpro.

scholarly journals Ligand deconstruction: Why some fragment binding positions are conserved and others are not

2015 ◽  
Vol 112 (20) ◽  
pp. E2585-E2594 ◽  
Author(s):  
Dima Kozakov ◽  
David R. Hall ◽  
Stefan Jehle ◽  
Lingqi Luo ◽  
Stefan O. Ochiana ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Hot Spot ◽  
Binding Mode ◽  
Binding Potential ◽  
Binding Modes ◽  
Affinity Ligand ◽  
Ligand Binding Sites ◽  
Free Energy Of Binding

Fragment-based drug discovery (FBDD) relies on the premise that the fragment binding mode will be conserved on subsequent expansion to a larger ligand. However, no general condition has been established to explain when fragment binding modes will be conserved. We show that a remarkably simple condition can be developed in terms of how fragments coincide with binding energy hot spots—regions of the protein where interactions with a ligand contribute substantial binding free energy—the locations of which can easily be determined computationally. Because a substantial fraction of the free energy of ligand binding comes from interacting with the residues in the energetically most important hot spot, a ligand moiety that sufficiently overlaps with this region will retain its location even when other parts of the ligand are removed. This hypothesis is supported by eight case studies. The condition helps identify whether a protein is suitable for FBDD, predicts the size of fragments required for screening, and determines whether a fragment hit can be extended into a higher affinity ligand. Our results show that ligand binding sites can usefully be thought of in terms of an anchor site, which is the top-ranked hot spot and dominates the free energy of binding, surrounded by a number of weaker satellite sites that confer improved affinity and selectivity for a particular ligand and that it is the intrinsic binding potential of the protein surface that determines whether it can serve as a robust binding site for a suitably optimized ligand.

Sign in / Sign up

Export Citation Format

Share Document