Free Energy Predictions of Ligand Binding to an α-Helix Using Steered Molecular Dynamics and Umbrella Sampling Simulations

Marzinek, Jan K.; Bond, Peter J.; Lian, Guoping; Zhao, Yanyan; Han, Lujia; Noro, Massimo G.; Pistikopoulos, Efstratios N.; Mantalaris, Athanasios

doi:10.1021/ci500164q

Cited by 20 publications

(12 citation statements)

References 62 publications

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“…Skin-PAMPA results can be used to prioritize and rank different Chen et al, 2008a). With the mechanistic modeling approach, the transport and disposition properties of epithelia can be determined separately, e.g., by molecular dynamics simulation of chemical binding to keratin at the sub-cellular level (Marzinek et al, 2014). This represents significant progress of simple permeability models.…”

Section: Synthetic Membrane Systemsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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SummaryModels of the outer epithelia of the human body -namely the skin, the intestine and the lung -have found valid applications in both research and industrial settings as attractive alternatives to animal testing. A variety of approaches to model these barriers are currently employed in such fields, ranging from the utilization of ex vivo tissue to reconstructed in vitro models, and further to chip-based technologies, synthetic membrane systems and, of increasing current interest, in silico modeling approaches. An international group of experts in the field of epithelial barriers was convened from academia, industry and regulatory bodies to present both the current state of the art of non-animal models of the skin, intestinal and pulmonary barriers in their various fields of application, and to discuss research-based, industry-driven and regulatory-relevant future directions for both the development of new models and the refinement of existing test methods. Issues of model relevance and preference, validation and standardization, acceptance, and the need for simplicity versus complexity were focal themes of the discussions. The outcomes of workshop presentations and discussions, in relation to both current status and future directions in the utilization and development of epithelial barrier models, are presented by the attending experts in the current report.

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Section: Synthetic Membrane Systemsmentioning

confidence: 99%

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Gordon

Daneshian

Bouwstra

et al. 2015

ALTEX

124

103

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“…Modelling of dermal absorption of chemicals has recently been improved by modelling the transport and disposition kinetics of chemical compounds in multilayered skin at the cellular level . Molecular dynamics simulation of chemical binding to keratin at the subcellular level can be used to model transport and disposition properties of epithelia . This represents significant improvement to earlier permeability models that were not acceptable from a regulatory point of view .…”

Section: Expectations—current and Future Developmentsmentioning

confidence: 99%

Skin toxicology and 3Rs—Current challenges for public health protection

Riebeling

Luch

Tralau

2018

Experimental Dermatology

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Driven by the fast paced development of complex test systems in vitro, mass spectrometry and omics, we finally have the tools to unravel the molecular events that underlie toxicological adversity. Yet, timely regulatory adaptation of these new tools continues to pose major challenges even for organs readily accessible such as skin. The reasons for this encompass a need for conservatism as well as the need of tests to serve an existing regulatory framework rather than to produce scientific knowledge. It is important to be aware of this in order to align regulatory skin toxicity with the 3R principles more readily. While most chemical safety testing is still based on animal data, regulatory frameworks have seen a strong push towards non-animal approaches. The endpoints corrosion, irritation, sensitisation, absorption and phototoxicity, for example, can now be covered in vitro with the corresponding test guidelines (TGs) being made available by the OECD. However, in vitro approaches tend to be more reductionist. Hence, a combination of several tests is usually preferable to achieve satisfying predictivity. Moreover, the test systems and their combined use need to be standardised and are therefore subject not only to validation but also to the ongoing development of so-called integrated approaches to testing and assessment (IATAs). Concomitantly, skin models are being refined to deliver the complexity required for increased applicability and predictivity. Given the importance of regulatory applicability for 3R-derived approaches to have a long-lasting impact, this review examines the state of regulatory implementation and perspectives, respectively.

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“…However, US itself does not provide the dissociation path. Therefore, enhanced sampling methods, such as steered molecular dynamics simulation (SMD) [13][14][15][16], adaptive biasing force (ABF) [17] and metadanamics [18], are often used to provide the dissociation pathway that can be used as initial conformations for the intensive biased sampling for US. A number of methods have been proposed to improve the accuracy of US, such as the use the constrained schemes to alleviate sampling limitation [19][20][21], or the combination with other method like Markov model to improve the convergence [22].…”

Section: Introductionmentioning

confidence: 99%

Evaluating the accuracy of the umbrella sampling plots with different dissociation paths, conformational changes, and structure preparation

You

Tang

2017

Preprint

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The kinetics of ligand dissociation has been found to be crucial for a good drug candidate. Therefore, examining the underlying free energy profile of the dissociation that governs the kinetics becomes important. Umbrella sampling (US), a widely used free energy calculation method, has long been used to explore the dissociation process of ligand-receptor systems. The potential of mean force (PMF) computed from US seems to always produce binding affinity and energy barriers that more or less agree with experiments. However, such PMFs are influenced by many practical aspects, like the method used to generate the initial dissociation pathway, collective variables (CVs) that used to describe the reaction coordinate (RC), and how intensive the sampling is in the conformational space restrained by the CVs. These critical factors were rarely studied. Here we applied US to study the dissociation processes of β-cyclodextrin (β-CD) and p38α complex systems. For β-CD, we used three different β-CD conformations to generate the dissociation path manually. For p38α, we generated the dissociation pathway using accelerated molecular dynamics (AMD) followed by conformational relaxing with short conventional molecular dynamics (MD), steered molecular dynamics (SMD) and manual pulling. We found that even for small β-CD complexes, different β-CD conformations will alter the height of the PMF and different dissociation directions result in appearance/disappearance of local minima. SMD poorly samples the residue sidechain movement, leading to overestimated height of PMF. On the other hand, the AMD pathway relaxed by short conventional MD sampled more accurate structures, resulting in reasonable PMF.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/169532 doi: bioRxiv preprint first posted online 3 Introduction Free energy is an important quantity that characterizes chemical and biological processes. The change of free energy governs the directionality and extent of chemical reactions. Free energy decomposes into enthalpy and entropy, where determination of entropy is challenging both experimentally and computationally. For these reasons, it is one central task for computational chemist to achieve accurate calculation of free energy, especially the free energy profile along a chemical process [1][2][3]. A variety of free energy calculation methods have been developed in the past decades, such as perturbation theory [4], thermodynamic integration [5], umbrella sampling [6], and partition function from density of states [7], and provided insights into various chemical and biological systems [8,9]. Among these methods, umbrella sampling (US) is a conceptually straightforward, computationally efficient and reliable one that computes the potential of mean force (PMF) based on rigorous probability calculations [6]. It requires a well-defined reaction coordinate (RC) represented by one or a few collective ...

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Free Energy Predictions of Ligand Binding to an α-Helix Using Steered Molecular Dynamics and Umbrella Sampling Simulations

Cited by 20 publications

References 62 publications

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Non-animal models of epithelial barriers (skin, intestine and lung) in research, industrial applications and regulatory toxicology

Skin toxicology and 3Rs—Current challenges for public health protection

Evaluating the accuracy of the umbrella sampling plots with different dissociation paths, conformational changes, and structure preparation

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