Resources generated with partial support from the NIH
The open source code of
NAMD 2.8 of the University of Illinois and its earlier versions are the MD engines we use to conduct most of our
in silico
experiments. The C++ modules of our additions and modifications to NAMD
as well as tcl scripts are available to all academic resarchers for free. URLs
for downloading them will be sent to you upon your request by emailing
Liao.Chen@utsa.edu.
Research with partial support from the NIH
-
Theoretical formulation has been firmly established for the
fluctuation-dissipation theorem (FDT) of the Brownian dynamics (BD) and the FDT
of Langevin dynamics (LD). BD-FDT relates the free-energy difference between two
equilibrium states A and B to the irreversible work measurements along the
non-equilibrium paths along which the system is pulled (steered) from A to B and
back from B to A. The efficiency and accuracy of the FDT’s have been proven for
several biophysical systems whose free-energies have been well determined in
experiments and/or by other far more expensive computational approaches. This
research is of fundamental importance and significant because all biochemical
and biophysical processes are driven by free-energy gradients. The available
computational methods in the current literature are either too expensive
(requiring unrealistically long simulation time) or too inaccurate for realistic
biophysical models such as kinesin-1-microtule-nucleotide system consisting of
hundreds of thousands of atoms. For details, click
http://JiLLL.utsa.edu/GM84834/fdt.html. Click here for the free-energy landscape of the
benzene-T4L system and here for a movie of water
transport through GlpF.
- Hydration energy of methane has been computed by using the
PI’s BD-FDT. In silico experiments have been conducted, pulling the methane
molecule into and out of a box water and measuring work done by the pulling
force along the each pulling path. The results of the BD-FDT approach with 6 nanoseconds
of simulations are in perfect agreement with the extremely long (7.2 μs)
simulation based on the thermodynamic integration approach. Both results are
excellent agreement with in vitro experiments. The details can be found at
http://JiLLL.utsa.edu/GM84834/methane.html.
- Kinesin-ADP association/binding energy has been computed
through in silico experiments of pulling ADP out of and into the cavity in one
of the two heads of kinesin-1. The measurements of work along the pulling paths
are transformed into the free-energy profile shown below (free energy vs
center-of-mass of ADP). The details are available at
http://JiLLL.utsa.edu/GM84834/3kin-adp.html.
- Elasticity of kinesin-1 in physiological saline is a key
element of the 3D model of the motor protein. The two heads and the stalk are
steered into various angles between the three. The free energies are computed by
the means of BD-FDT. With BD-FDT, we are exploring the free-energy surface (FES)
instead of the potential energy surface (PES) of the model system. This is more
important because the PES is a step further away from the reality than the FES.
A representative free-energy landscape of kinesin-1 in physiological saline is
shown below. The results can be found at
http://JiLLL.utsa.edu/GM84834/3kin-elasticity.html.
- Binding/unbinding of amphetamine and methylamphetamine to
antibody scFv (PDF here).
- Mercury inhibits the L170C mutant of Aquaporin Z by making waters clog the water
channel, Y. B. Zhang, Y. B. Cui, and L. Y. Chen, Biophysical Chemistry, (2011)
DOI:
10.1016/j.bpc.2011.07.006.
- Diffusion in periodic potentials with path integral hyperdynamics, T. Ikonen,
M. D. Khandkar, L. Y. Chen, S. C. Ying, and T. Ala Nissila, Phys. Rev. E (2011). DOI: 10.1103/PhysRevE.00.006700.
- Interaction of a two-transmembrane-helix peptide with lipid bilayers and
dodecyl sulfate micelles, Robert Renthal, Lorenzo Brancaleon, Isaac Pena,
Frances Silva, and Liao Y. Chen, Biophysical Chemistry (2011) DOI:10.1016/j.bpc.2011.08.005.
-
Insights into the mechanisms of the selectivity filter of Escherichia coli aquaporin Z, G. Hu, L. Y. Chen, and J. Wang, Journal of Molecular Modeling, (2012) DOI: 10.1007/s00894-012-1379-2.
- Glycerol Modulates Water Permeation through Escherichia coli Aquaglyceroporin
GlpF, L. Y. Chen (2012) submitted.
Among aquaglyceroporins that transport both
water and glycerol across the cell membrane, Escherichia coli glycerol uptake
facilitator (GlpF) is the most thoroughly studied. However, one question
remains: Does glycerol modulate water permeation? This study answers this
fundamental question by determining the chemical-potential profile of glycerol
along the permeation path through GlpF’s conducting pore. There is a deep well
near the Asn-Pro-Ala (NPA) motifs (dissociation constant 14μM) and a barrier
near the selectivity filter (10.1 kcal/mol above the well bottom). This profile
owes its existence to GlpF’s perfect steric arrangement: The glycerol-protein
van der Waals interactions are attractive near the NPA but repulsive elsewhere
in the conducting pore. In light of the single-file nature of waters and
glycerols lining up in GlpF’s amphipathic pore, it leads to the following
conclusion: Glycerol modulates water permeation in the micromolar range. At mM
concentrations, GlpF is glycerol-saturated and a glycerol residing in the well
occludes the conducting pore. Therefore, water permeation is fully correlated to
glycerol dissociation that has an Arrhenius activation barrier of 6.5 kcal/mol.
Validation of this theory is based on the existent in vitro data, some of which
have not been given the proper attention they deserved: The Arrhenius activation
barriers were found to be 7 kcal/mol for water permeation and 9.6 kcal/mol for
glycerol permeation; The presence of up to 100 mM glycerol did not affect the
kinetics of water transport with very low permeability, in apparent
contradiction with the existent theories that predicted high permeability (0 M
glycerol). As an addition to the science of hydrogen-bonding of waters and
glycerols in the conducting pore, this study demonstrates that the van der Waals
interactions between the GlpF and a glycerol play a distinctive biological role.
The size of the conducting pore is such that a region exists near the NPA motifs
where the VDW interactions between the GlpF and a glycerol are attractive. This
precise steric arrangement of GlpF causes the glycerol’s chemical potential
there to be lower than its bulk level and, therefore, a bound state of glycerol
exists deep inside the single-file channel.
- In silico
study of biophysical functions of AQP5: Effects and affinity of the
central pore-occluding lipid and permeation of water, oxygen, and
carbon-dioxide, Zhang YB, Chen, LY,
(2012) in preparation.
Because of its
roles in human physiology, Aquaporin V (AQP5), a major intrinsic protein, has
been a subject of many in vitro studies. In particular, a recent experiment
produced its crystal structure at 2.0 Å resolution, which is in a tetrameric
conformation consisting of four protomers. Another recent experiment showed that
it facilitates not only water permeation but also gas permeation through the
cell membrane. In this article, we present an in silico study of AQP5 to
elucidate the mechanistic details of its facilitation of water and gas
permeation. We identify the passway for gas permeation by examining all
possibilities: the central pore formed by the four protomers , the interstices
between two adjacent protomers, and the spaces, if any, between the protein and
the membrane lipids. The conclusion is that nonpolar gas molecules (O2 or CO2)
permeate through AQP5's hydrophobic central pore. Along the permeation path
through the unoccluded central pore, the Arrhenius activation barriers are
around 3 kcal/mol for both O2 and CO2. However, the x-ray structure clearly
tells us that a lipid, PS6, is bound to AQP5 that occludes the central pore.
Computing the lipid's chemical-potential along its dissociation path, we find
that PS6 is an inhibitor with an IC50 in the nM range. Examining the
effects of PS6's binding to and dissociating from AQP5's the central pore, we
conclude that PS6 does not alter water permeation through AQP5.
