Peters Research Group
Affiliated Centers
Massey Cancer Center
Center for the Study of Biological Complexity
Our research spans from detailed biomolecular
computations and mathematical methods to experimental studies, including
preclinical and laboratory experiments. Our
goals are to apply fundamental concepts in science, engineering, and
mathematics to solve contemporary problems across the physical and life
sciences.
Our overall research topics fall into several main categories
1. Protein-Protein Interactions
We
have developed an all-atom energy landscape mapping tool for protein-protein
interactions, which we called OpenContact.
This open-source computational tool allows the determination of the most
dominant atom-atom interactions among the residues of protein-protein binding
partners. It has been successfully used
to determine druggable "hot spots" and to design peptide biomimetics
aimed at disrupting aberrant interactions.
Recently, it has been used to study the fundamental binding behavior of
amyloid beta fibrils present in Alzheimer's disease, and it is currently being
used to design small molecule inhibitors to the fibril formation process. The OpenContact computational package is
compiled and wrapped in a Python GUI making it a user friendly open-source tool
with no user knowledge required of the details of the all-atom biomolecular
computations.
The
OpenContact page for downloads and information on use is given below. OpenContact is also available world-wide
through the Protein Data Bank (PDB) under their third party software tools
repository and, as a fully compiled code under Windows O.S., it runs locally on
any PC desktop. The current open source
license for OpenContact is the popular Sleepy Cat license. The site link below includes a READ ME file
for its use as well as all source codes and force field data parameter files
for the interested user. We also added plotting and spread sheet features to
aid the user in interpretation and further analysis of output results. The plotting feature, which uses the open
source Matplotlib, generates "heat" maps that "light up"
the dominant interaction sites. The user
can also "lower the energetic ceiling" in order to hone in on
dominant interactions, such as hydrogen bonding sites.
Beta-Release of
OpenContact V3.0, which includes DNA-Protein Interactions, is scheduled for
this Fall 2020
Bastidas,O.H.,
Green, B., Sprague, M., and Peters, M.H, Few Ramachandran Angle Changes Provide
Interaction Strength Increase in Aβ42 versus Aβ40 Amyloid Fibrils, Sci. Rep., 6, 36499 (2016). DOI: 10.1038/srep36499.
Krall,A., Brunn, J., Kankanala, S., and Peters, M.H. (2014). A
Simple Contact Mapping Algorithm for
Indentifying Peptide Mimetics in Protein-Protein Interaction Partners. Proteins. Structure, Function, and Bioinformatics,
82, 2253-2262.
Other research areas of
Protein-Protein Interactions by our group include:
dynamics of PPI’s via implicit solvent methods
The
study of protein flexibility or dynamic protein conformational changes is
critically important to the understanding of protein function including, for
example, folding/misfolding, ligand-receptor signaling, enzymatic reactions, and
protein-DNA interactions, to name a few.
We
have developed an Implicit Solvent method for the study of biological molecular
flexibility and conformational changes. Briefly,
the implicit solvent method is based on an all-atom approach that utilizes
three important elements: 1) the physical and electrostatic effects of water
molecules are averaged and thus not treated explicitly, 2) inter-atomic
interaction forces associated with the protein are based on established force
field models, and 3) protein atomic displacement trajectories are calculated
based on integration of the Langevin equation that rigorously follow from the
N-body Liouville equation noted above. The first element involves a short-time
averaging of the host solvent dynamics leading to implicit solvent functions
such as position dependent dielectric constant, apolar implicit solvent forces
and diffusion tensors for the protein ligands or subunits (Fig. 2). The second element is accomplished via all
atom force-field which accounts for the charge and polar (Coulombic) and
non-polar (Lennard-Jones or LJ) atom-atom interactions. The third element involves considering both
deterministic and stochastic effects of Brownian motion of the solute or ligand
induced by the presence of the solvent as they are prescribed in the Langevin
equation.
Peters, M.H. (2011).
Langevin Dynamics for the Transport of Flexible Biological Macromolecules in Confined
Geometries, J. Chem. Phys., 134, 025105 (1-11).
fragment discovery algorithms
Infectious disease from
viral agents continues to represent one of the most significant health threats
to society. The ability of these agents to mutate, transform, and develop
across species makes them a formidable opponent to the development of
therapeutics, diagnostics, and vaccines aimed at their debilitation. The
development of vaccines to emerging forms of viral agents represents a methodical
and coordinated response to reduce outbreaks and pandemics. However, the speed at which vaccines can be
developed and produced on a large, global scale across a spectrum of
ever-changing pathogens is a significant drawback to their use. Here we take a radically different
large-scale, multiprocessor computational approach based on a fragment
discovery and annealing algorithm to generate small molecule, designer peptide
candidates for specific antigen recognition.
In turn, promising computationally designed peptide candidates can be
further studied experimentally and potentially produced on a large scale
through modern, relatively low-cost recombinant and ex-vivo peptide production
methods.
Peters, M.H., Targeting HIV-1 Envelop Proteins Using
a Fragment discovery All-Atom Computational Algorithm, Current Enzyme Inhibition, 13, 1-7 (2017). DOI: 10.2174/1573408012666160725095854.
protein folding
When
nascent proteins are manufactured in cellular ribosomes, they quickly “fold” or
collapse into structures that are responsible for their particular
function. For example, the protein may
fold to expose a particular segment or set of residues to the “outside world” that
leads to its function or role as a self-recognition element. Folding must be precise even though the
overall structure appears highly chaotic (twisted like a telephone cord). We are using IS methods to attempt to tackle
the protein folding problem and sort out the essential dynamic elements that
are necessary to accomplish this “order out of chaos” state.
2. Drug Development: Alzheimer’s Disease and Inhibiting Apoptotic
Pathways in Cancer
a-beta amyloid plaque inhibitors
We
have used our detailed energy mappings to develop small molecular weight
peptides that both disrupt the oligomer/fibril formation process by binding to
key adhesive contact points in the Aβ42 monomers but also have the potential to
cross the so-called blood brain barrier (BBB).
We have carried out numerous in-vitro studies that demonstrate the
potential of these inhibitors at treating AD, and we have furthered our
mechanistic understandings of amyloid fibril formation through dynamic biomolecular computational studies.
anti-apoptotic inhibitors in cancer
World-wide, an estimated 500,000 women die each year from breast
cancer. Chemotherapeutic agents in the
treatment of breast cancer are based on the particular cancer cell type, such
as drugs that specifically target the HER2 protein for HER2-positive breast
cancers. Breast cancers can develop
chemo-resistance through the blocking of cell death pathways, such as the
blocking of apoptotic pathways (anti-apoptotic behavior).
We have developed a
potential, novel peptide inhibitor to Bcl-2 Associated Anthanogen (BAG-1) which
is associated with anti-apoptotic pathways prevalent in a variety of cancer
cell types including, most notably, breast cancers. An all-atom, dominant energy landscape mapping
of BAG-1 to its HSP-70/HSC-70 (Heat Shock Protein 70 and its conjugate) binding
partner identified a helical peptide segment from the binding domain of HSC-70. Experimental kinetic binding studies
demonstrated that this peptide binds to BAG-1 in the pico-molar range. Subsequently, we augmented the helical
peptide with a poly-arginine CPP (cell penetrating peptide) and demonstrated
dose-dependent increases in apoptosis in a number of hematological cancer cell
lines and primary patient AML cells.
BAG-1 could be a
critical target in multimode chemotherapeutic approaches aimed at breast
cancer. In fact, BAG-1 inhibition via
knockdown studies was recently demonstrated to synergistically enhance the
effects of Trastuzumab in HER2 positive breast cancer cell lines
3.
Statistical Mechanics and Foundations of the Second Law
We
also work in fundamental areas of science and mathematics in addition to the
applied areas described above. Our fundamental
research includes the molecular foundations of the Second Law of Thermodynamics
(entropy) and fundamental aspects of statistical mechanics (perturbation theory).
Peters, M.H., Generalized Entropy Generation Expressions in Gases
Entropy 2019, 21, 330; doi:10.3390/e21040330
Peters, M. H., Molecular Thermodynamics and Transport Phenomena. Complexities of Scales in Space and Time, McGraw-Hill, NY, 2005.
Contact: mpeters@vcu.edu
601 West Main Street Department of Chemical and Life Science Engineering Virginia Commonwealth University, Richmond, VA 23284 804-828-7790