| Chen Zeng , Ph.D. |
Assistant Professor
Department of Physics, Columbian College of Arts and Sciences |
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| Chen Zeng has a vigorous research program in structural biology
by using large-scale computational modeling of proteins at molecular
level. Two particular research areas that are of current interest
to them are de novo protein design and systematic studies of
protein-ligand binding. They are described below. A/ Protein
Design: Despite the daunting diversity of protein sequences
of 20 different amino acids (e.g., there are approximately 100,000
different types of proteins found in humans alone), it has been
estimated that there are only about 1000 distinct protein folds
in nature. Why nature favors such a relatively small number
of folds is the question that motivates their research in this
project. Their objective is to uncover the common features shared
among these popular folds in nature and to incorporate these
features in their computational modeling to design proteins
that possess novel structures and/or enzymatic activities. One
of several highly designable folds they have identified for
proteins of length around 30 residues is the beta-alpha-beta
fold. This fold is indeed prevalent as a small part embedded
in natural proteins. Their results, however, suggest that this
fold should be a fundamental unit, i.e., it is stable by itself
with a suitable amino acid sequence. Through further detailed
all-atom-force modelling and sequence analysis, they identified
a sequence of 33 amino acids, synthesized it, and carried out
the structural analysis via NMR in collaboration with our colleagues
at Beijing University, P.R. China. The preliminary experimental
results suggest that this sequence indeed takes on the predicted
beta-alpha-beta motif. Although it is a proof of principle at
this stage, it nonetheless opens the intriguing possibility
of systematically identifying all small independent and fundamental
units (folds) from which most of the present natural proteins
may come about via fusion and natural selection. Such a systematic
tabulation will also provide a potentially very useful database
for drug design. Much of the software developed in the research
on protein design is also a powerful simulation tool for investigating
protein-protein and protein-peptide interactions. B/ Protein-Peptide
Binding Site(s): Human immunodeficiency virus type 1 (HIV-1)
encodes a small protein, Tat, that varies from 86 to 101 amino
acids for different virus strains and plays an important role
in viral gene expression. Tat is believed to function at both
transcription initiation and elongation. To control the growth
and replication of the HIV-1 virus, researchers have zeroed
in on Tat and sought to disrupt its function by introducing
suitable inhibitors. Dr. Kashanchi and coworkers have discovered
a five-residue peptide that is a strong inhibitor. Furthermore
to understand more precisely the function of the five-residue
Tat peptide, researchers have found that it binds strongly with
a number of regulatory enzymes, among them cyclin dependent
kinase 2 (CDK2). The structure of CDK2 is known by X-ray crystallography
and has been deposited in the Protein Data Bank (PDB), yet the
binding site for the Tat peptide is currently not known. Our
initial computational project attempts to first discover the
binding site on CDK2 (the docking problem) and then redesign
the ligand peptide: to make it smaller (thus more viable as
a drug) and/or bind more strongly (the design problem). |
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