Electrostatic Steering of Substrate to Acetylcholinesterase: Analysis of Field FluctuationsStanislaw T. Wlodek, Tongye Shen and J. Andrew McCammonBiopolymers, Vol. 53, Issue 3, pp. 265-271 (2000) [PubMed 10679631]Based on previous molecular dynamics simulation results for
acetylcholinesterase (AChE) dimer, we calculate and analyse the
electrostatic field fluctuations around the enzyme. The results show
that dynamic features of the electrostatic field favor attraction of the
positively-charged substrate. An internet link to an animation of the
results is also provided (http://mccammon.ucsd.edu/gallery/"
target="_blank" class="ref">http://mccammon.ucsd.edu/gallery/).
Calculations of Relative Hydration Free Energies: A Comparative Study Using Thermodynamic Integration and an Extrapolation Method Based on a Single Reference StateTiziana Z. Mordasini and J. Andrew McCammonJournal of Physical Chemistry B, Vol. 104, No. 2, pp. 360-367 (2000)
The relative hydration free energies of a series of organic molecules
were calculated from Molecular Dynamics (MD) simulations using an
extrapolation method in combination with soft-core potential scaling.
This technique consists in first generating one single long trajectory
using an unphysical reference state and in using afterwards this
trajectory for the estimation of the free energy difference between
several molecules. First, we investigated the accuracy of the method for
the deletion of small functional groups. A trajectory from an MD
simulation of pyrogallol (1,2,3-trihydroxybenzene) was used to calculate
by extrapolation the free energy changes for the mutations of
pyrogallol, catechol and phenol to benzene in water and in vacuo. The
results were compared to those obtained by thermodynamic integration, to
experimental data and to values calculated using a semi-empirical
method. In a second step, increasingly larger mutations were studied, in
order to investigate the limitations of the method. The influence of
various simulation parameters (choice of the unphysical reference state,
simulation length, soft-core scaling parameter a) on the final free
energy values was examined. Benzene derivatives with hydroxyalkly and/or
bulky functional groups of increasing sizes were mutated into benzene.
The results for simulations both in water and in vacuo were compared to
the free energy results obtained by thermodynamic integration and to the
experimental values of similar molecules. The results showed that for
small mutations (deletion of functional groups with up to three atoms)
the extrapolation method is reliable. However, the free energies
calculated for the deletion of larger functional groups showed different
accuracy levels depending on the chosen simulation parameters. For the
largest mutations the thermodynamic integration method also showed
convergence problems. This study therefore demonstrated the usefulness
of the extrapolation method for molecules of similar size, but showed
the difficulties of obtaining reliable results for molecules that
substantially differ from each other.
Accommodating Protein Flexibility in Computational Drug DesignHeather A. Carlson and J. Andrew McCammonMolecular Pharmacology, Vol. 57, Issue 2, pp. 213-218 (2000) [PubMed 10648630]The need to account for the dynamic behavior of a receptor has long been
recognized as a complicating factor in computational drug design. The
use of a single, rigid protein structure - usually from an X-ray crystal
structure - is still the standard in most applications. The choice to
use a single protein structure is usually based on speed. For example,
if a large database of compounds is to be screened for binding affinity,
several conformers of each compound will be compared to each protein
configuration. Though it is more accurate to use many representative
protein configurations, it quickly becomes a very slow process to screen
each conformer of each ligand against each protein configuration. It is
usually impractical to attempt such prohibitively slow calculations, as
there is an unfortunate but necessary trade off between speed and
accuracy in computer modeling. Only recently have advanced methods been
introduced to aid in a more accurate description of protein flexibility
and its influence on ligand recognition. This has been aided by the
exponential growth in the speed of computer processors, available RAM,
and disk capacity - all of which are rapidly becoming less expensive.
Here, we explain the need for accommodating an ensemble of protein
configurations in drug design and the computational methods available
for generating and manipulating that dynamic information. Most of the
applications discussed are improvements in ligand docking or in the
generation of pharmacophore models for database searching.
NWChem: Exploiting Parallelism in Molecular SimulationsT.P. Straatsma, M. Philippopoulos and J.A. McCammonComputer Physics Communications, Vol. 128, Issues 1-2, pp. 377-385 (2000)
NWChem is the software package for computational chemistry on massively
parallel computing systems developed by the High Performance
Computational Chemistry group for the Environmental Molecular Sciences
Laboratory. The software provides a variety of modules for quantum
mechanical and classical mechanical simulations. This article describes
the design of the molecular dynamics simulation module, which is based
on a domain decomposition, and provides implementation details on the
data and communication structure and how the code deals with the
complexity of atom redistribution and load balancing.
Developing a Dynamic Pharmacophore Model for HIV-1 IntegraseHeather A. Carlson, Kevin M. Masukawa, Kathleen Rubins, Fredric D. Bushman, William L. Jorgensen, Roberto D. Lins, James M. Briggs and J. Andrew McCammonJournal of Medicinal Chemistry, Vol. 43, No. 11, pp. 2100-2114 (2000) [PubMed 10841789]The "dynamic" pharmacophore model presented in this study is the first
reported receptor-based pharmacophore model for HIV-1 integrase. The
development of dynamic pharmacophore models is a new method that
accounts for the inherent flexibility of a target active site and aims
to reduce the entropic penalty associated with changes in conformation
and flexibility of the active site upon binding a ligand. A molecular
dynamics (MD) simulation is used to describe the flexibility of the
uncomplexed protein. Many conformational models of the protein are saved
from the MD simulations and are used in a series of multi-unit search
for interacting conformers (MUSIC) simulations. MUSIC is a multiple-copy
method, recently made available in the BOSS program, that is used to
determine binding sites for functional groups that complement the active
site. The coordinates from each protein conformation are overlaid, and
conserved binding sites in the active sites are identified. The dynamic
pharmacophore model is comprised of the conserved binding sites. Here,
the dynamic model is compared to known inhibitors of the integrase as
well as a three-point, ligand-based pharmacophore model from the
literature that is a subset of the dynamic model. A second, "static"
pharmacophore model was determined in the standard fashion, using only
the crystal structure that was used to initialize the MD studies.
Inhibitors thought to potentially bind in the active site of HIV-1
integrase fit the dynamic model, but not the static model, implying that
new compounds determined with the dynamic model have a greater potential
for inhibition than those identified with the static model. Furthermore,
we have identified a set of compounds from the Available Chemicals
Database that fit the dynamic pharmacophore model. Experimental testing
of these compounds has revealed several new inhibitory compounds, but
they are weak inhibitors and point to a need to improve the specificity
of the model for this system.
Lateral Diffusion of Membrane Proteins in the Presence of Static and Dynamic Corrals - Suggestions For Appropriate ObservablesFrank L.H. Brown, David M. Leitner, J. Andrew McCammon and Kent R. WilsonBiophysical Journal, Vol. 78, No. 5, pp. 2257-2269 (2000) [PubMed 10777724]We consider the possibility of inferring the nature of cytoskeletal
interaction with transmembrane proteins via optical experiments such as
single particle tracking (SPT) and near-field scanning optical
microscopy (NSOM). In particular, we demonstrate that it may be possible
to differentiate between static and dynamic barriers to diffusion by
examining the time dependent variance and higher moments of protein
population inside cytoskeletal "corrals". Simulations modeling Band 3
diffusion on the surface of erythrocytes provide a concrete
demonstration that these statistical tools might prove useful in the
study of biological systems.
Molecular Dynamics Simulations of a Polyalanine Octapeptide under Ewald Boundary Conditions: Influence of Artificial Periodicity on Peptide ConformationWolfgang Weber, Philippe H. Hünenberger and J. Andrew McCammonJournal of Physical Chemistry B, Vol. 104, No. 15, pp. 3668-3675 (2000)
Ewald and related mesh methods are nowadays routinely used in
explicit-solvent simulations of solvated biomolecules, although they
impose an artificial periodicity in systems which are inherently
non-periodic. In the present study, we investigate the consequences of
this approximation for the conformational equilibrium of a polyalanine
octapeptide (with charged termini) in water. We report three
explicit-solvent molecular dynamics simulations of this peptide in cubic
unit cells of edges L = 2, 3 and 4 nm, using the
particle-particle-particle mesh (P³ M) method for handling
electrostatic interactions. The initial configuration of the peptide is
α-helical. In the largest unit cell (L = 4 nm), the helix
unfolds quickly towards configurations with shorter end-to-end
distances. By contrast, in the two smaller unit cells (L = 2 and
L =3 nm), the α-helix remains stable during two
nanoseconds. Backbone fluctuations are somewhat larger in the medium
(L = 3 nm) compared to the smallest unit cell. These differences
are rationalized using a continuum electrostatic analysis of
configurations from the simulations. These calculations show that the
α-helical conformation is stabilized by artificial periodicity
relative to any other configuration sampled during the trajectories.
This artificial stablilization is larger for smaller unit cells, and is
responsible for the absence of unfolding in the two smaller unit cells
and the reduced backbone fluctuations in the smallest unit cell. These
results suggest that artificial periodicity imposed by the use of
infinite periodic (Ewald) boundary conditions in explicit-solvent
simulations of biomolecules may significantly perturb the potentials of
mean force for conformational equilibria, and even in some cases invert
the relative stabilities of the folded and unfolded states.
Domain Motions of EF-G Bound to the 70S Ribosome: Insights From a Hand-Shaking Between Multi-Resolution StructuresWilly Wriggers, Rajendra K. Agrawal, Devin Lee Drew, J. Andrew McCammon and Joachim FrankBiophysical Journal, Vol. 79, No. 3, pp. 1670-1678 (2000)
Molecular modeling and information processing techniques were combined
to refine the structure of translocase (EF-G) in the ribosome-bound form
against data from cryo-electron microscopy (cryo-EM). We devised a novel
multi-scale refinement method based on vector quantization and
force-field methods that gives excellent agreement between the flexibly
docked structure of GDP · EF-G and the cryo-EM density map at
17Å resolution. The refinement reveals a dramatic "induced fit"
conformational change on the 70S ribosome, mainly involving EF-G's
domains III, IV, and V. The rearrangement of EF-G's structurally
preserved regions, mediated and guided by flexible linkers, defines the
site of interaction with the GTPase-associated center of the ribosome.
Quantum-Dynamical Picture of a Multi-Step Enzymatic Process. Reaction Catalyzed by Phospholipase A2P. Ba&Biophysical Journal, Vol. 79, No. 3, pp. 1253-1262 (2000) [PubMed 10968989]A Quantum-Classical Molecular Dyamics model (QCMD), applying explicit
integration of the time-dependent Schroedinger equation (QD) and
Newtonian equations of motion (MD), is presented. The model is capable
of describing quantum dynamical processes in complex biomolecular
systems. It has been applied in simulations of a multi-step catalytic
process carried out by phospholipase A
2 in its active site.
The process includes quantum-dynamical proton transfer from a water
molecule to histidine localized in the active site, followed by a
nucleophilic attack of the resulting OH
- group on a carbonyl
carbon atom of a phospholipid substrate, leading to cleavage of an
adjacent ester bond. The process has been simulated using a parallel
version of the QCMD code. The potential energy function for the active
site is computed using an Approximate Valence Bond (AVB) method. The
dynamics of the key proton is described either by QD or classical MD.
The coupling between the quantum proton and the classical atoms is
accomplished
via Hellmann-Feynman forces, as well as the
time-dependence of the potential energy function in the Schroedinger
equation (QCMD/AVB model). Analysis of the simulation results using an
Advanced Visualization System revealed a correlated rather than a
stepwise picture of the enzymatic process. It is shown that an sp²
-> sp³ configurational change at the substrate carbonyl carbon
is mostly responsible for triggering the activation process
HIV-1 Integrase Inhibitor Interactions at the Active Site: Prediction of Binding Modes Unaffected by Crystal PackingChristoph A. Sotriffer, Haihong Ni and J. Andrew McCammonJournal of the American Chemical Society, Vol. 122, No. 25, pp. 6136-6137 (2000)
Crystal structures of an inhibitor or substrate bound to an enzyme
generally constitute the preferred starting point for structure based
drug design. Although this approach is normally very effective for the
rational optimization of lead compounds, limitations can arise when the
crystal environment significantly affects the observed binding mode and
leads to differences with respect to the solution phase. Such situations
have the potential to be misleading for working hypotheses about
enzyme-inhibitor interaction. Here, we outline a computational docking
study of these issues for HIV-1 integrase (IN), the enzyme responsible
for the integration of reversely transcribed viral DNA into host cell
DNA.
Active Site Binding Modes of HIV-1 Integrase InhibitorsChristoph A. Sotriffer, Haihong Ni and J. Andrew McCammonJournal of Medicinal Chemistry, Vol. 43, No. 22, pp. 4109-4117 (2000) [PubMed 11063607]Using the crystal structure of the first complex of the HIV-1 integrase
catalytic core domain with an inhibitor bound to the active site,
structural models for the interaction of various inhibitors with
integrase were generated by computational docking. For the compound of
the crystallographic study, binding modes unaffected by crystal packing
have recently been proposed. Although a large search region was used for
the docking simulations, the ligands investigated here are found to bind
preferably in similar ways close to the active site. The binding site is
formed by residues 64-67, 116, 148, 151-152, 155-156, and 159, as well
as by residue 92 in case of the largest ligand of the series. The
coherent picture of possible interactions of small-molecule inhibitors
at the active site provides an improved basis for structure-based ligand
design. The recurring motif of tight interaction with the two lysine
residues 156 and 159 is suggested to be of prime importance.