Nav: Home

Chirality of vitamin-D derivative affects the protonation states of its receptor protein

October 31, 2018

Researchers at Toyohashi University of Technology, in cooperation with researchers at Teijin Pharma Ltd. and Teikyo University, have highlighted the possibility that chirality of vitamin-D derivatives can affect the protonation states of histidine residues in the vitamin-D receptor protein via ab initio molecular simulations and biomedical analyses. This finding emphasizes that protonation states should be considered more precisely in molecular simulations, when investigating specific interactions between candidate drugs and target proteins related to disease pathogenesis.

Vitamin-D is recognized to play many important roles in the onset of immunological diseases, as well as the regulation of calcium level in the blood. These physiological actions caused by active vitamin-D are triggered by the specific interaction of active vitamin-D with the vitamin-D receptor (VDR); many types of vitamin-D derivatives have been developed as potent ligands against VDR. The binding affinity between human VDR and vitamin-D derivatives has been reported to depend significantly on the chirality of the derivative.

However, the reason for the dependence has not been clarified, which makes it a bottleneck in the development of novel and potent drugs against immunological diseases, whose onset is related to the activation of VDR.

Now, researchers at the Department of Computer Science and Engineering at Toyohashi University of Technology and at Teijin Pharma Ltd. and Teikyo University have demonstrated the possibility of the chirality of vitamin-D derivative to affect the protonation states of histidine residues in the VDR protein based on the results evaluated by state-of-the art molecular simulations and the K computer of RIKEN.

Researchers have observed the specific interactions between VDR and some vitamin-D derivatives with different chiralities using ab initio fragment molecular orbital (FMO) calculations. The FMO results reveal that two histidine residues in the VDR contribute significantly to the binding of the VDR with the derivatives and that the protonation states of these residues can affect the specific interactions. Therefore, the researchers considered the other possible protonation states of these histidine residues and determined the most stable states using the ab initio FMO calculations. The results illustrated, for the first time, the possibility that the difference in the chiralities of vitamin-D derivatives can induce changes in protonation states of the histidine residues in the VDR that exists near the derivative. Due to this change in the protonation state, the derivatives can bind more strongly to the VDR and can thus produce more stable complexes with it.

This finding provides an important and essential warning for the molecular simulations to consider protonation states of histidine residues in proteins more precisely while investigating the specific interactions between proteins and ligands.

"We have used sophisticated molecular simulations and the K computer to find that the protonation states of the histidine residues in the VDR change significantly with alterations in the chirality of ligand", explains Associate Professor Noriyuki Kurita, "Since histidine residues exist in many proteins involved in the pathogenesis of diseases, we should consider their protonation states more precisely via in silico drug design based on molecular simulations."

The first author, graduate student Yuta Terauchi, said, "Our final goal is to develop novel and potent drugs capable of activating VDR based on our ab initio molecular simulations, as well as on the basis of biomedical studies performed by our collaborators."

The authors are participating in an in silico drug design consortium - the fragment molecular orbital drug design (FMODD) consortium - in which various researchers from universities, drug companies, and national institutes are investigating the specific interactions between disease-related proteins and many types of candidate drugs using ab initio molecular simulations based on the FMO method and the K computer. Similar molecular simulations are underway now for a huge number of vitamin-D derivatives in order to propose novel ligands for VDR, which can act as candidate for potent drugs against immunological diseases, such as cancer.
-end-
Acknowledgements:

A part of this research was undertaken during activities of the FMODD consortium. A part of the results was obtained using the K computer (project ID: hp170183 and hp180147).

References:

Yuta Terauchi, Rie Suzuki, Ryosuke Takeda, Ittetsu Kobayashi, Atsushi Kittaka, Midori Takimoto-Kamimura and Noriyuki Kurita (2018).

Ligand chirality can affect histidine protonation of vitamin-D receptor: ab initio molecular orbital calculations in water.

Journal of Steroid Biochemistry and Molecular Biology, in press.

(DOI: https://doi.org/10.1016/j.jsbmb.2018.09.020).

Further information

Toyohashi University of Technology
1-1 Hibarigaoka, Tempaku
Toyohashi, Aichi Prefecture, 441-8580, JAPAN
Inquiries: Committee for Public Relations
E-mail: press@office.tut.ac.jp

Toyohashi University of Technology, which was founded in 1976 as a National University of Japan, is a leading research institute in the fields of mechanical engineering, advanced electronics, information sciences, life sciences, and architecture.

Website: http://www.tut.ac.jp/english/

Toyohashi University of Technology

Related Proteins Articles:

Coupled proteins
Researchers from Heidelberg University and Sendai University in Japan used new biotechnological methods to study how human cells react to and further process external signals.
Understanding the power of honey through its proteins
Honey is a culinary staple that can be found in kitchens around the world.
How proteins become embedded in a cell membrane
Many proteins with important biological functions are embedded in a biomembrane in the cells of humans and other living organisms.
Finding the proteins that unpack DNA
A new method allows researchers to systematically identify specialized proteins called 'nuclesome displacing factors' that unpack DNA inside the nucleus of a cell, making the usually dense DNA more accessible for gene expression and other functions.
A brewer's tale of proteins and beer
The transformation of barley grains into beer is an old story, typically starring water, yeast and hops.
New tool for the crystallization of proteins
ETH researchers have developed a new method of crystallizing large membrane proteins in order to determine their structure.
New interaction mechanism of proteins discovered
UZH researchers have discovered a previously unknown way in which proteins interact with one another and cells organize themselves.
When proteins shake hands
Protein nanofibres often have outstanding properties such as a high stability, biodegradability, or antibacterial effect.
Proteins' fluorescence a little less mysterious
Rice University scientists use simulations to understand the mechanism behind a popular fluorescent protein used to monitor signals between neurons.
New study suggests health benefits of swapping animal proteins for plant proteins
Substituting one to two servings of animal proteins with plant proteins every day could lead to a small reduction in the three main cholesterol markers for cardiovascular disease prevention, a new study suggests.
More Proteins News and Proteins Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

Accessing Better Health
Essential health care is a right, not a privilege ... or is it? This hour, TED speakers explore how we can give everyone access to a healthier way of life, despite who you are or where you live. Guests include physician Raj Panjabi, former NYC health commissioner Mary Bassett, researcher Michael Hendryx, and neuroscientist Rachel Wurzman.
Now Playing: Science for the People

#544 Prosperity Without Growth
The societies we live in are organised around growth, objects, and driving forward a constantly expanding economy as benchmarks of success and prosperity. But this growing consumption at all costs is at odds with our understanding of what our planet can support. How do we lower the environmental impact of economic activity? How do we redefine success and prosperity separate from GDP, which politicians and governments have focused on for decades? We speak with ecological economist Tim Jackson, Professor of Sustainable Development at the University of Surrey, Director of the Centre for the Understanding of Sustainable Propserity, and author of...
Now Playing: Radiolab

An Announcement from Radiolab