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Computational Research in Molecular Chemistry
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 (" target="_blank" class="ref">
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 A2 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.
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