Molecular Applications

(To open PDF: 5 sig figs of π)

Four major research projects:
(1) Isotope Effects on the Biocatalysis by Phosphodiesterase (in signal-transduction pathways)
(2) Avian and Swine Influenza (H5N1 and H1N1 flu viruses)
(3) SARS Virus
(4) Green Biotechnology: Biodegradable Light-Emitting Electronics

1. Isotope Effects on the Biocatalysis by Phosphodiesterase (in signal-transduction pathways)

The protein-enzyme phosphodiesterase (PDE) is an important regulator in signal-transduction pathways (YouTube for signal-transduction pathways).  For example, the well-known drug Viagra® (Chinese name: 偉哥/威而鋼) inhibits specifically PDE for a treatment of erectile dysfunction.

The role of PDE in signal transduction pathways is to terminate the signal responses by a biochemical reaction: hydrolysis of cyclic nucleotides (second messengers).  Previously, we have generated a two-dimensional (2D) quantum free-energy profile (a very important physical quantity in quantum biochemistry) to elucidate the reaction mechanism of the hydrolysis catalyzed by PDE [DOI] [PDF].

This time, by collaborating with the prestigious experimental group of Prof. Michael E. Harris at the Case Western Reserve University, we would like to precisely determine the structure of the rate-limiting transition state by computing isotope effects on the biocatalysis that agree with experimental results. Determining the structure of the rate-liming transition state could have a profound impact on the rational drug design (in molecular medicine), by manipulating regulations of signal responses.


2. Avian and Swine Influenza (H5N1 and H1N1 flu viruses)

Three influenza pandemics that killed tens of millions of people were respectively caused by new strains of flu in 1918, 1957, and 1968.  Lately, human beings have been dealing with two newest strains of influenza: 1. Avian H5N1 flu (Chinese name: 禽流感); 2. Swine H1N1 flu (Chinese name: 豬流感).

Avian influenza is extremely fatal.  Its incredible lethality is about ~60%.  By contrast, swine flu is not that deadly, though it is highly contagious that has made the World Health Organization (WHO) declare a new flu pandemic in June of 2009.

Hemagglutinin and neuraminidase are the two major viral protein enzymes in the proposed life cycle of the flu viruses.  As a result, different strains of flu are named in accordance with the subtypes of these two viral proteins (i.e., the “H” of H5 or H1 is Hemagglutinin; the “N” of N1 is Neuraminidase).

Hemagglutinin is responsible for the binding of virus to a host cell.  H1 binds to the upper part of the respiratory tract, while H5 attaches to the lower part.  Neuraminidase terminates the linkage between the cell receptor and the virus, so that the virus can target and invade another cell.  Many anti-flu drugs, e.g., Tamiflu (Chinese name: 特敏福) and Relenza (Chinese name: 樂感清), are specifically designed to inhibit this neuraminidase for slowing down the rapid spread of the virus.

In fact, biochemical reactions are the essence during the binding and release steps of the virus catalyzed by the viral enzyme hemagglutinin and neuraminidase, respectively.  In order to shed some light on the reaction mechanisms, we plan to explicitly simulate these chemical steps by generating quantum free-energy profiles (very important physical quantities in quantum biochemistry).  In addition, we would also compute isotope effects that match with experimental values for determining the structures of the rate-limiting transition states, which in turn could tremendously help to rationally design a more effective anti-flu drug (in molecular medicine).

3. SARS Virus

The full name of SARS is severe acute respiratory syndrome, which is quite similar to the syndrome of pneumonia.  Since the first case was reported in November of 2002, we had the SARS epidemics within several months.  Subsequently, for the first time, the World Health Organization (WHO) has issued the Global Alert in March of 2003 due to the fearful fatality (~10%) and the high contagiousness of the disease.  Medical-care staff can easily be infected by SARS if no extreme cautious measures are taken.

SARS is caused by human SARS coronavirus (SARS-CoV).  In the life cycle of SARS-CoV, there is a protease enzyme playing a crucial role in the viral transcription and replication events.  As a result, inhibiting the proteolysis (a chemical reaction to breakdown a protein) catalyzed by this protease is a popular way in rationally designing an effective drug against SARS-CoV.  Understanding the mechanism underlying the proteolysis should be a big help for finding a new effective drug.

In order to unravel the reaction mechanism behind the proteolysis catalyzed by the protease, we plan to explicitly simulate the protein-breakdown processes by generating quantum free-energy profiles (very important physical quantities in quantum biochemistry).  We would also like to test the effectiveness of a series of anti-SARS drugs by computing the relative binding energies (in molecular medicine).

4. Green Biotechnology: Biodegradable Light-Emitting Electronics

Biotechnology can certainly also be used for applications in Green Energy.  Currently, we are working closely with the prestigious experimental group of Prof. Shu-Kong So at the Hong Kong Baptist University to study biodegradable light-emitting electronics.  We hope that by investigating and understanding the origins of these light-emitting electronics at the molecular level, brighter and more efficient biodegradable devices can be invented and fabricated.