Andreas W. Götz, Mark J. Williamson,
, Duncan Poole, Scott Le Grand, Ross C. Walker
We present an implementation of generalized Born implicit solvent all-atom classical molecular dynamics (MD) within the AMBER program package that runs entirely on CUDA enabled NVIDIA graphics processing units (GPUs). We discuss the algorithms that are used to exploit the processing power of the GPUs and show the performance that can be achieved in comparison to simulations on conventional CPU clusters. The implementation supports three different precision models in which the contributions to the forces are calculated in single precision floating point arithmetics but accumulated in double precision (SPDP), or everything is computed in single precision (SPSP), or double precision (DPDP). In addition to performance we have focused on understanding the implications of the different precision models on the outcome of implicit solvent MD simulations. We show results for a range of tests including the accuracy of single point force evaluations and energy conservation as well as structural properties pertainining to protein dynamics. The numerical noise due to rounding errors within the SPSP precision model is sufficiently large to lead to an accumulation of errors which can result in unphysical trajectories for long timescale simulations. We recommend the use of the mixedprecision SPDP model since the numerical results obtained are comparable with those of the full double precision DPDP model and the reference double precision CPU implementation but at significantly reduced computational cost. Our implementation provides performance for GB simulations in a single desktop that is on par with, and in some cases exceeds that of traditional supercomputers.
Jennifer S. Forbey, Xinzhu Pu,
The plant secondary metabolite papyriferic acid (PA) deters browsing by snowshoe hares (
). However, the physiological mechanism that reduces browsing remains unknown. We used pharmacological assays and molecular modeling to test the hypothesis that inhibition of succinate dehydrogenase (SDH) is a mode of action (MOA) of toxicity of PA in snowshoe hares. We tested this hypothesis by measuring the effect of PA on the activity of SDH in liver mitochondria isolated from wild hares. In addition, we used molecular modeling to determine the specific binding site of PA on SDH. We found that PA inhibits SDH from hares by an uncompetitive mechanism in a dose-dependent manner. Molecular modeling suggests that inhibition of SDH is a result of binding of PA at the ubiquinone binding sites in complex II. Our results provide a MOA for toxicity that may be responsible for the concentration-dependent anti-feedant effects of PA. We propose that snowshoe hares reduce the dose-dependent toxic consequences of PA by relying on efflux transporters and metabolizing enzymes that lower systemic exposure to dietary PA.
Symmetry Breaking in Linear ZnCl2+: A Theoretical Study
Wenli Zou, Dong Xu
, Peter Zajac, Andrew L. Cooksy, Isaac B. Bersuker, Yang Liu, and James E. Boggs
J. Mol. Struct.
Distinct Glycan Topology for Avian and Human Sialopentasaccharide Receptor Analogues upon Binding Different Hemagglutinins: A Molecular Dynamics Perspective
The four lowest excited states
are calculated using the EOMIP-CCSD method and the spectroscopic
constants are reported. It is found that all the states have linear
structures, while some states are noncentrosymmetric with two equivalent global minima due to
the pseudo Jahn–Teller effect. The computed barriers between the two
minima are 88 and 169 cm−1, respectively, being much smaller
and more reliable than the previous published multi-configurational
results because of inaccurate treatment of the static correlation in the
latter. For the ground
state, anharmonic vibrational levels are also simulated using the
finite element method. It shows that the configuration of the vibronic
ground state is also noncentrosymmetric.
, E. Irene Newhouse, Rommie E. Amaro, Hsing C. Pao, Lily S. Cheng, Phineus R.L. Markwick, J. Andrew McCammon, Wilfred W. Li and Peter W. Arzberger
J. Mol. Biol.
Hemagglutinin (HA) binds to sialylated glycans exposed on the host cell surface in the initial stage of avi
an influenza virus infection. It
has been previously hypothesized that glycan topology plays a critical role
in the human
of avian flu virus
such as the
potentially pandemic H5N1.
Comparative molecular dynamics
are complementary to experimental techniques, including glycan
microarray, to understand the mechanism of species-specificity switch
better. The examined systems comprise explicitly solv
ated trimeric form
of avian H3, H5, and swine H9 in complex with avian and human
glycan receptor analogues-LSTa (α-2,3-linked lactoseries
tetrasaccharide a) and LSTc (α-2,6-linked lactoseries tetrasaccharide
c), respectively. The glycans adopted distinct topological profiles with
inducible torsional angles when bound to different HAs. The corresponding receptor binding domain amino acid
contact profiles were also distinct. Avian H5 was able to accommodate
LSTc in a tightly “folded umbrella”-like topology through interactions
with all five sugar residues. After considering conformational entropy,
the relative binding free-energy changes, calculated using the molecular
mechanics-generalized Born surface area technique, were in agreement
with previous experimental findings and provided insights on
electrostatic, van der Waals, desolvation, and entropic contributions to
HA-glycan interactions. The topology profile and the relative abundance
of free glycan receptors may influence receptor binding
kinetics. Glycan composition and topological changes upon binding
different HAs may be important determinants in species-specificity
Mechanism of Glycan Receptor Recognition and Specificity Switch for Avian, Swine, and Human Adapted Influenza Virus Hemagglutinins: A Molecular Dynamics Perspective
E. Irene Newhouse, Dong Xu
, Phineus R. L. Markwick, Rommie E. Amaro, Hsing C. Pao, Kevin J. Wu, Maqsudul Alam, J. Andrew McCammon and Wilfred W. Li
J. Am. Chem. Soc.
Hemagglutinins (HA’s) from duck, swine, and human influenza viruses have
previously been shown to prefer avian and human glycan receptor
analogues with distinct topological profiles, pentasaccharides LSTa
(α-2,3 linkage) and LSTc (α-2,6 linkage), in comparative molecular
dynamics studies. On the basis of detailed analyses of the dynamic
motions of the receptor binding domains (RBDs) and interaction energy
profiles with individual glycan residues, we have identified ~30
residue positions in the RBD that present distinct profiles with the
receptor analogues. Glycan binding constrained the conformational space
sampling by the HA. Electrostatic steering appeared to play a key role
in glycan binding specificity. The complex dynamic behaviors of the
major SSE and trimeric interfaces with or without bound glycans
suggested that networks of interactions might account for species
specificity in these low affinity and high avidity (multivalent)
interactions between different HA and glycans. Contact frequency,
energetic decomposition, and H-bond analyses revealed species-specific
differences in HA−glycan interaction profiles, not readily discernible
from crystal structures alone. Interaction energy profiles indicated
that mutation events at the set of residues such as 145, 156, 158, and
222 would favor human or avian receptor analogues, often through
interactions with distal asialo-residues. These results correlate well
with existing experimental evidence, and suggest new opportunities for
simulation-based vaccine and drug development.
Characterizing Loop Dynamics and Ligand Recognition in Human- and Avian-Type Influenza Neuraminidases via Generalized Born Molecular Dynamics and End-Point Free Energy Calculations
Rommie E. Amaro, Xiaolin Cheng, Ivaylo Ivanov, Dong Xu
and J. Andrew McCammon
J. Am. Chem. Soc.
The comparative dynamics and inhibitor binding free energies of group-1
and group-2 pathogenic influenza A subtype neuraminidase (NA) enzymes
are of fundamental biological interest and relevant to structure-based
drug design studies for antiviral compounds. In this work, we present
seven generalized Born molecular dynamics simulations of avian (N1)- and
human (N9)-type NAs in order to probe the comparative flexibility of
the two subtypes, both with and without the inhibitor oseltamivir bound.
The enhanced sampling obtained through the implicit solvent treatment
suggests several provocative insights into the dynamics of the two
subtypes, including that the group-2 enzymes may exhibit similar motion
in the 430-binding site regions but different 150-loop motion. End-point
free energy calculations elucidate the contributions to inhibitor
binding free energies and suggest that entropic considerations cannot be
neglected when comparing across the subtypes. We anticipate the
findings presented here will have broad implications for the development
of novel antiviral compounds against both seasonal and pandemic
Solving the Vibrational Schrodinger Equation on an Arbitrary Multidimensional Potential Energy Surface by the Finite Element Method
Dong Xu, Jernej Stare and Andrew L. Cooksy
Comp. Phys. Comm., 180 (11):2079-209 (2009).
A computational protocol has been developed to solve the bounded vibrational Schrödinger equation for up to three coupled coordinates on any given effective potential energy surface (PES). The dynamic Wilson G-matrix is evaluated from the discrete PES calculations, allowing the PES to be parametrized in terms of any complete, minimal set of coordinates, whether orthogonal or non-orthogonal. The partial differential equation is solved using the finite element method (FEM), to take advantage of its localized basis set structure and intrinsic scalability to multiple dimensions. A mixed programming paradigm takes advantage of existing libraries for constructing the FEM basis and carrying out the linear algebra. Results are presented from a series of calculations confirming the flexibility, accuracy, and efficiency of the protocol, including tests on FHF−, picolinic acid N-oxide, trans-stilbene, a generalized proton transfer system, and selected model systems.
Ensemble-Based Virtual Screening Reveals Potential Novel Antiviral Compounds for Avian Influenza Neuraminidase
Lily S. Cheng, Rommie E. Amaro, Dong Xu
, Wilfred W. Li, Peter W. Arzberger and J. Andrew McCammon
J. Med. Chem.
(13): 3878–3894 (2008).
Avian influenza virus subtype H5N1 is a potential pandemic threat with human-adapted strains resistant to antiviral drugs. Although virtual screening (VS) against a crystal or relaxed receptor structure is an established method to identify potential inhibitors, the more dynamic changes within binding sites are neglected. To accommodate full receptor flexibility, we use AutoDock4 to screen the NCI diversity set against representative receptor ensembles extracted from explicitly solvated molecular dynamics simulations of the neuraminidase system. The top hits are redocked to the entire nonredundant receptor ensemble and rescored using the relaxed complex scheme (RCS). Of the 27 top hits reported, half ranked very poorly if only crystal structures are used. These compounds target the catalytic cavity as well as the newly identified 150- and 430-cavities, which exhibit dynamic properties in electrostatic surface and geometric shape. This ensemble-based VS and RCS approach may offer improvement over existing strategies for structure-based drug discovery.
Statistical Cluster Analysis of Pharmaceutical Solvents
and Nancy Redman-Furey
Intl. J. Pharm.
, 339:175-188 (2007).
High efficiency in polymorph screening and crystallization optimization
can be gained by judicious selection of solvents for the study design.
Examination of all 57 (classes 2 and 3) pharmaceutical solvents may
enable a complete study design but is costly in terms of time and
resources. Based on a 17 descriptor dataset specifically constructed for
all the classes 2 and 3 pharmaceutical solvents recognized by the
International Conference of Harmonization (ICH), an optimal two-stage
cluster analysis was carried out together with principal component
analysis as a dimensionality and colinearity reduction pre-processor.
Both hierarchical average linkage cluster analysis and non-hierarchical K
cluster analysis converged on a 20-cluster solution with strong
statistical criteria support and excellent agreement in cluster
memberships, which can be reasonably interpreted from a chemical
perspective. This 20-cluster solution is offered as an option for design
of more efficient solid state screening studies. Rather than designing a
polymorph screen to include all 57 solvents, the inclusion of a single
member from each of the 20 clusters would be expected to adequately
represent the full range of solvent properties exhibited by the entire
57 member solvent set.
Ab Initio Study of the Torsional Motion in Tolane
and Andrew L. Cooksy
J. Mol. Struct. THEOCHEM
, 815:119-125 (2007).
Accurate prediction of the torsional barrier height in tolane is
achieved by systematically extrapolating to the Dunning complete basis
set limit at the MP2 level with a spin-component-scaled correction. The
zero-point energy correction is calculated at the B98/cc-pVDZ level
based on a benchmark test using the experimental data for benzene. The
final calculated barrier height is 202 cm−1
, in agreement
with the observed value. The correct barrier height enables the
vibrational energy levels and other spectroscopic properties to be
determined accurately through numerical integration of the torsional
Schrödinger equation. This study provides a nearly complete
computational solution to the torsional problem in tolane and may aid
the exploration of torsional motions in similar molecules.
Alkylation of Phenol with Tert-butyl Alcohol Catalyzed by Large Pore Zeolites
Kui Zhang, Huaibin Zhang, Genhui Xu, Shouhe Xiang, Dong Xu
, Shangyuan Liu and Hexuan Li
Applied Catalysis A: General
, 207:183-190 (2001).
The tert-butylation of phenol was investigated over various zeolite catalysts using tert-butyl alcohol as alkylating agent in a down-flow tubular reactor at atmospheric pressure. Zeolite HY was beneficial to the reaction. The important variables affecting the activity and selectivity of zeolite HY, such as reaction temperature, space velocity and molar ratios of tert-butyl alcohol to phenol, were studied. Zeolite HY hydrothermally treated at high temperatures (above 873 K) was unfavorable to the reaction. The activity and selectivity of zeolite HY were not sensitive to its crystallite diameter change. In the alkylation of phenol with tert-butyl alcohol over zeolite HY catalyst, the suitable reaction temperature range was from 398 to 438 K. Lower reactant molar ratios were beneficial to p-TBP and o-TBP, while higher ones were helpful to produce 2,4-DTBP. Lower space velocities (WHSV (h−1
)), i.e. <1.66 (based on phenol) were beneficial to the reaction. The present study shows that zeolite HY has a potential application in the production of tert-butyl phenols with high activity and 2,4-DTBP selectivity.
Alkylation of Phenol with Tert-butyl Alcohol Catalysed by Zeolite Hβ
Kui Zhang, Dong Xu
, Huaibin Zhang, Shangyuan Liu, Changhua Huang, Heshou Xiang and Hexuan Li
Applied Catalysis A: General
, 166:89-95 (1998).
The catalytic properties of zeolite beta in the tert-butylation of phenol are reported. The influence of various reaction parameters such as temperature, space velocity, molar ratio of the reactants are discussed. Medium acid sites on zeolite Hβ are advantageous in producing p-TBP, and that of strong acid sites are helpful for the formation of 2,4-DTBP, while weak acid sites are effective in producing o-TBP. In order to enhance the selectivity of p-TBP, a proper reaction temperature (418 K), lower reactant ratio (molar ratio) and moderate acidities on zeolite Hβ are recommended. On the basis of the behaviour obtained in the cases mentioned, information about the reaction path models is provided.