Research
Introduction
To put it mildly, computers have changed many aspects of our lives. Nowhere is this more true than in the realm of science, where for over 60 years, investigators have been using computers to solve complex problems.
Although computers and science have been intertwined for decades now, their relationship has enjoyed a stimulating growth particularly over the past 10 years. With the advent of fast processors, larger memory storage, and feasible inter-hardware communication, today, even a modest desktop computer can perform many scientific calculations. The user no longer requires a warehouse full of machines for simple scientific tasks. Moreover, parallel programming codes and architecture make it possible for one to link up two or more desktop machines (or simply their processors), for even faster computing. In such a parallel fashion, even a small cluster can perform at the level of yesterday's supercomputer.
The other dramatic change that has occurred over the past 10 years is in the demographic of the computing community. What used to be a body of only "hard" scientists (physicists, engineers, mathematicians) now consists of investigators from many disciplines (even non-traditional sciences, like epidemiology, geography, and finance). Many subjects now reap the benefits of the predictions and modeling afforded by computational science. In due time, every discipline will have a significant computational component to it.
As evidenced by the 1998 Nobel Prize in Chemistry, computational science propels chemical thinking in the 21st century. Around the world, chemists harness various computational techniques to understand phenomena such as protein-ligand binding, macromolecular association, chemical reactivity, and molecular dynamics.
The McCammon Lab here at UCSD is at the forefront of this revolution in chemistry. Using the most advanced computational techniques, we have shed light on a diverse set of chemical topics, such as electrostatic steering, diffusion, ligand docking, free-energy calculations, and molecular dynamics. The following is some of the work that I have done here in the McCammon lab. Thanks for reading, and please feel free to email me with any comments, questions, or requests for prints.
Location of Inhibitors Bound to Group IVA Phospholipase A2 Determined by Molecular Dynamics and Deuterium Exchange Mass Spectrometry
John E. Burke; Arneh Babakhani, Alemayehu A. Gorfe, George Kokotos, Sheng Li, Virgil L. Woods, Jr. , J. Andrew McCammon, Edward E. Dennis. Journal of the American Chemical Society 2009, In press.
An analysis of group IVA (GIVA) phospholipase A2 (PLA2) inhibitor binding was conducted using a combination of deuterium exchange mass spectrometry (DXMS) and molecular dynamics (MD). Models of the GIVA PLA2 inhibitors pyrrophenone and the 2-oxoamide AX007 docked into the protein were designed on the basis of deuterium exchange results, and extensive molecular dynamics simulations were run to determine protein−inhibitor contacts. The models show that both inhibitors interact with key residues that also exhibit changes in deuterium exchange upon inhibitor binding. Pyrrophenone is bound to the protein through numerous hydrophobic residues located distal from the active site, while the oxoamide is bound mainly through contacts near the active site. We also show differences in protein dynamics around the active site between the two inhibitor-bound complexes. This combination of computational and experimental methods is useful in defining more accurate inhibitor binding sites and can be used in the generation of better inhibitors against GIVA PLA2.
A Virtual Screening Study of the Acetylcholine Binding Protein using a Relaxed-complex Approach
Arneh Babakhani, Todd T. Talley, Palmer Taylor, J. Andrew McCammon. Computational Biology and Chemistry 2009, 33, 160-170.
The nicotinic acetylcholine receptor (nAChR) is a member of the ligand-gated ion channel family and is implicated in many neurological events. Yet, the receptor is difficult to target without high-resolution structures. In contrast, the structure of the acetylcholine binding protein (AChBP) has been solved to high resolution, and it serves as a surrogate structure of the extra-cellular domain in nAChR. Here we conduct a virtual screening study of the AChBP using the relaxed-complex method, which involves a combination of molecular dynamics simulations (to achieve receptor structures) and ligand docking. The library screened through comes from the National Cancer Institute, and its ligands show great potential for binding AChBP in various manners. These ligands mimic the known binders of AChBP; a significant subset docks well against all species of the protein and some distinguish between the various structures. These novel ligands could serve as potential pharmaceuticals in the AChBP/nAChR systems.
Thermodynamics of Peptide Insertion and Aggregation in a Lipid Bilayer.
Arneh Babakhani, Alemayehu A. Gorfe, Judy E. Kim, J. Andrew McCammon. Journal of Physical Chemistry B 2008, 112, 10528-10534.
A variety of biomolecules mediate physiological processes by inserting and reorganizing in cell membranes, and the thermodynamic forces responsible for their partitioning are of great interest. Recent experiments provided valuable data on the free energy changes associated with the transfer of individual amino acids from water to membrane. However, a complete picture of the pathways and the associated changes in energy of peptide insertion into a membrane remains elusive. To this end, computational techniques supplement the experimental data with atomic-level details and shed light on the energetics of insertion. Here, we employed the technique of umbrella sampling in a total 850 ns of all-atom molecular dynamics simulations to study the free energy profile and the pathway of insertion of a model hexapeptide consisting of a tryptophan and five leucines (WL5). The computed free energy profile of the peptide as it travels from bulk solvent through the membrane core exhibits two minima: a local minimum at the water-membrane interface or the head group region; and a global minimum at the hydrophobic-hydrophilic interface close to the lipid glycerol region. A rather small barrier of roughly 1 kcal/mol exists at the membrane core, which is explained by the enhanced flexibility of the peptide when deeply-inserted. Combining our results with those in the literature, we present a thermodynamic model for peptide insertion and aggregation which involves peptide aggregation upon contact with the membrane at the solvent-lipid head group interface.
H-ras protein in a bilayer: Interaction and structure perturbation.
Alemayehu A. Gorfe, Arneh Babakhani, J. Andrew McCammon. Journal of the American Chemical Society 2007, 129, 12280-12286.
Ras GTPases become functionally active when anchored to membranes by inserting their lipid modified side chains. Their role in cell division, development, and cancer has made them targets of extensive research efforts, yet the mechanism of membrane insertion and the structure of the resulting complex remain elusive. Recently, the structure of the full-length H-ras protein in a DMPC bilayer has been computationally characterized. Here, the atomic interactions between the H-ras membrane anchor and the DMPC bilayer are investigated in detail. We find that the palmitoylated cysteines and Met182 have dual contributions to membrane affinity: hydrogen bonding by their amides and van der Waals interaction by their hydrophobic side chains. The polar side chains help maintain the orientation of the anchor. Although the overall structure of the bilayer is similar to that of a pure DMPC, there are localized perturbations. These perturbations depend on the insertion depth and backbone localization of the anchor, which in turn is modulated by the catalytic domain and the linker. The pattern of anchor amide-DMPC phosphate/carbonyl hydrogen bonds and the flexibility of Palm184 are important in discriminating between different modes of ras-DMPC interactions. The results provide structural arguments in support of the proposed participation of ras in the organization of membrane nanoclusters.
Free energy profile of H-ras membrane anchor upon membrane insertion.
Alemayehu A. Gorfe, Arneh Babakhani, J. Andrew McCammon. Angewandte Chemie International Edition 2007, 46, 8234-8237.
Peptide insertion, positioning, and stabilization in a membrane: Insight from an all-atom molecular dynamics simulation
Arneh Babakhani, Alemayehu A. Gorfe, Justin Gullingsrud, Judy E. Kim, J. Andrew McCammon. Biopolymers 2007, 85, 5-6, 490-497.
Peptide insertion, positioning, and stabilization in a model membrane are probed via an all-atom molecular dynamics simulation. One peptide (WL5) is simulated in each leaflet of a solvated dimyristoylglycero-3-phosphate (DMPC) membrane. Within the first 5 ns, the peptides spontaneously insert into the membrane and then stabilize during the remaining 70 ns of simulation time. In both leaflets, the peptides localize to the membrane interface, and this localization is attributed to the formation of peptide-lipid hydrogen bonds. We show that the single tryptophan residue in each peptide contributes significantly to these hydrogen bonds; specifically, the nitrogen heteroatom of the indole ring plays a critical role. The tilt angles of the indole rings relative to the membrane normal in the upper and lower leaflets are approximately 26° and 54°, respectively. The tilt angles of the entire peptide chain are 62° and 74°. The membrane induces conformations of the peptide that are characteristic of -sheets, and the peptide enhances the lipid ordering in the membrane. Finally, the diffusion rate of the peptides in the membrane plane is calculated (based on experimental peptide concentrations) to be approximately 6 Å2/ns, thus suggesting a 500 ns time scale for intermolecular interactions.
Computational investigation of pressure profiles in lipid bilayers with embedded proteins.
Justin Gullingsrud, Arneh Babakhani, and J. Andrew McCammon. Molecular Simulation 2006, 32, 831838.
The distribution of surface tension within a lipid bilayer, also referred to as the lateral pressure profile, has been the subject of theoretical scrutiny recently due to its potential to radically alter the function of biomedically important membrane proteins. Experimental measurements of the pressure profile are still hard to come by, leaving first-principles all-atom calculations of the profile as an important investigative tool. We describe and validate an efficient implementation of pressure profile calculations in the molecular dynamics package NAMD, capable of distinguishing between internal, bonded and nonbonded contributions as well as those of selected atom groups. The new implementation can also be used in conjunction with Ewald summation for long-range electrostatics, improving the accuracy and reproducibility of the calculated profiles. We then describe results of the calculation of a pressure profile for a simple protein–lipid system consisting of melittin embedded in a DMPC bilayer. While the lateral pressure in the protein–lipid system is nearly the same as that of the bilayer alone, partitioning of the lateral pressure by atom type revealed substantial perturbation of the pressure profile and surface tension in an asymmetric manner.