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The Theoretical and Computational Biophysics Group - Yesterday, Today, and Tomorrow

The Theoretical and Computational Biophysics Group (TCBG) has existed for 22 years. In briefest terms, its mission can be characterized as equipping biomedical researchers with a unique research instrument, the computational microscope and utilizing the microscope for discoveries in Biophysics of the Living Cell.

The Computational Microscope
Figure 1.1: The computational microscope - an
emerging research instrument in cell biology.

Over the last three decades, computational biologists have developed the ability to model cellular processes. Key approaches in this pursuit are molecular visualization, sequence analysis, and molecular dynamics. In this role, computing offers access to databases of rapidly increasing size and value; it complements observation, transforming static crystallographic structures through simulation into dynamic systems. Increasingly often, computing correctly predicts missing structural data. During its maturation phase, computational biology was considered a valuable, but limited, tool, the limits being mainly due to lack of accuracy and restriction in size and time scales. Computational biology has now matured such that its descriptions of cellular systems and processes compare, in many cases, favorably with observation. The degree of realism reached lets us at the TCBG consider our approach to be a new kind of microscopy. In a recent essay [1] (see also [2]), we present this view and showcase discoveries made through the computational microscope in the field of cellular mechanics.

The computational microscope consists of software—the Group's programs NAMD (nanoscale molecular dynamics) and VMD (visual molecular dynamics). The computational microscope can be readily duplicated and handed to biomedical researchers.

There are 20,000 NIH-funded researchers, and approximately 100,000 others, who registered as new users of VMD or NAMD during just the last five years. Continued development of the computational microscope costs approximately $2 million in NIH funding per year, but this cost translates into only about $100 per year for each NIH-funded user. This modest expenditure yields two valuable programs that play key roles in users’ research, as stated in survey responses; many students and professional researchers worldwide also benefit from these programs, multiplying the impact of the software in finding cures for diseases that affect all mankind. Through intense face-to-face training, through a thousand pages of tutorials, and through direct (Group-to-user) and indirect (user-to-user) assistance, the Group facilitates effective use of VMD and NAMD and the computational microscope that they constitute.

Vital Statistics and achievements
Figure 1.2: Theoretical and Computational Biophysics Group - vital statistics and achievements (to September, 2011).

Figure 1.2 introduces the Group through its vital statistics and achievements, while Fig. 1.3 shows the Group personnel. The Group, comprising twelve NIH-funded staff, five faculty members, and their students and postdocs, brings together leading computational biology research and leading software development. Other NIH and funds from NSF support cell biology research. To illustrate the research strength of the Group, we note that there have been 37,000 citations to its publications that went into print since 1990. The breadth and depth of the research performed at the Group are reflected in monthly highlights published prominently on the Group's web site, with 87 highlights from the 2006–2011 period.

Members of the Theoretical and Computational Biophysics Group
Figure 1.3: Members of the Theoretical and Computational Biophysics Group (September, 2011).

Integration of Activities

The Group is considered a leader in computer-based biomedical research for its discoveries in cellular mechanics, membrane biophysics, quantum biology (vision, photosynthesis), and nanoengineering (biosensor development). The Group's high profile led to many fruitful collaborations with experimental laboratories; in 2007–2011 we completed 33 collaborative projects with 52 joint publications. Some of the collaborations involve members of the intramural NSF-funded Center for the Physics of Living Cells. Our Group is closely involved in the NSF Center, where Schulten is co-director. The intense scientific research effort of our Group is a continuing impetus for our software development and has been instrumental to the success of VMD and NAMD. We expect that the Group's ongoing research involving world-renowned laboratories, will likewise be a driving force for improving our Group's software.

A further distinguishing strength of our Group is its location—the Beckman Institute for Advanced Science and Technology on our host university’s campus. Three essential aspects of the Beckman Institute should be noted. First, the Beckman Institute seeks to link science and engineering; this link is the heart of our Group that combines biomedical research and software engineering. The Beckman Institute offers an attractive setting for our experienced software developers as they find many peers around them with their skills highly valued. The high esteem in which we hold our technical staff has resulted in extremely low turnover; one cannot overestimate the value that motivation and expertise have in accomplishing ambitious development goals. Second, the Beckman Institute is strictly interdisciplinary; it is a discipline-neutral territory not dominated by any one particular academic department. In the case of our Group, we combine faculty, postdocs, and students from physics, biophysics, chemistry, biochemistry, and computer science. They share contiguous office space with each other and with the Group developers, leading to a continuous and constructive interaction between science and development. A key attribute in this regard is the strong 20-year link between our computer scientists and our physical and life scientists; not only does this link show up in the unique performance of NAMD and science breakthroughs, but it has also led to wide recognition, e.g., the Gordon Bell Prize, highly regarded in parallel computing. Third, the contiguous space the Group occupies is optimal for the purpose of communication between all personnel, with offices arranged around two wide open courtyards used for small and large meetings and spontaneous discussions. The space provides public areas for visitor workstations, excellent projection and conference facilities, a comfortable visitor center, and a library; research and development space of such high quality is rarely found elsewhere.

Lastly, we point out that the Group has been uniquely successful in betting on the right technology early. We cannot attribute this success to any particular factor, except that we judge solutions strictly on the basis of what benefits biomedical research (as opposed to being technologically interesting) and that we don't mind being bold. The Group was the first to embrace parallel computers for molecular dynamics, having even built its own sixty-processor parallel computer [3, 4] that contributed to our founding NIH grant. The Group, against the resistance of established computing centers, bet on computer clusters as the most cost-effective and efficient means of parallel computing in biomedicine; the Group also embraced modern software principles like the C++ programming language. It is hard to imagine today how our approach was ridiculed at the time. The Group added the program VMD to its molecular dynamics (MD) software, making VMD from the beginning a sister program to NAMD for analysis and visualization of MD trajectories. The combined power of VMD and NAMD facilitates successful biomolecular simulations for many biomedical researchers. The Group also selected graphics processing units (GPUs) for acceleration of NAMD and VMD, publishing an in-depth treatise on GPU acceleration in molecular modeling in 2007 [5], a highly cited paper years ahead of other similar attempts. One can summarize the role of the Group reflected in its history as follows: The Group brings key technological advances early to biomedical research. Without the Group, these advances would certainly also spill eventually into biomedical research, but at a slower pace and, most likely, not at the high level of quality and convenience that the Group software offers.

Rationale for the Group

The important role of computing in biomedical research and medical practice is hardly disputed today. Most expect that the role will grow in importance even further and wish for improvements in ease of use, reliability, and performance. Until recently such improvements were mainly driven by advances of computer hardware. However, today new hardware means more processors and cores; old software on new hardware may not yield improved performance. The key driver of advances in biomedical computing is therefore software development. The dominant role of software in the computer industry can be witnessed almost universally in the industry's recent success stories, ranging from Google to the iPad. Our Group's software focus promises, therefore, a great return on NIH funds as it converts commodity devices into highly valuable scientific instruments, for example, a laptop computer into the aforementioned computational microscope. Our past record shows that the Group does an excellent job in bringing about such conversion rapidly, with highly productive outcomes in terms of software releases. So far, the main macromolecular modeling software packages of the Group were VMD and NAMD; over the next funding period we will build upon VMD and NAMD, developing a suite of further modeling software focusing on cell-scale descriptions.

The Group targets a wide group of users with VMD and NAMD, from bench scientist to computational scientist, from student to expert. Our development strategy seeks to continuously balance the interests of general users, intermediate experts, and advanced users. Concretely, this implies that we adapt our programs to the platforms employed by the different user groups, e.g., Windows, MacOS, and Linux for the general user and the latest petaflop machine at Argonne National Laboratory for the most advanced users. In fact, platform adaptation for the benefit of the large user community is a major cost factor in our development effort, an activity that leads to gratitude from the many users of our software.

Technological Themes

With the rapid evolution of computing technology, the Group continually encounters new opportunities around its main technological themes. GPU-accelerated computing was an example of such an opportunity in 2007 [5], immediately exploited and continuously developed in VMD and NAMD. A more recent example is the use of solid state disks (SSDs) to read and write data at speeds within a factor ten of main memory (RAM) [6]. Overnight, SSD technology has transformed the capability for trajectory analysis in VMD, but it required a new trajectory file format and significant changes to VMD's internal data structures. A key bottleneck expected for petascale simulations, namely trajectory I/O, thus disappeared, but only after the Group's development investment. In the following the three main technological themes of the Group are presented.

Computational graphics. Molecular visualization has always been one of the most demanding applications for graphics processors. Accordingly, the development of our molecular graphics software package VMD has been a technological challenge requiring, over the last decade, adaptation from fixed function graphics accelerators to fully programmable graphics processing units (GPUs). For example, programmable shading, available in VMD since 2005, now permits enhanced transparent surfaces, giving users the opportunity to more clearly display structures docked into cryo-electron microscopy density maps. Today graphics programs do much more than display images, e.g., they analyze structural data and terabytes of simulation trajectories, carrying out for this purpose extensive general computing. Accordingly, VMD uses graphics accelerators for both visualization and general computing. In the future we expect computational graphics to continue offering new opportunities, in particular in the areas of interactive structural display and analysis, for example permitting display of dynamics images at video rates and photorealistic quality.

Parallel computing. For over two decades, parallel computing has been a consistent path to higher performance in all fields of computational science. Similarly, parallel computing has been the primary enabling technology of the Group since its inception, allowing dramatic and consistent increases in simulation size and timescale that will now extend to accuracy and sampling as well. The parallel scalability of the NAMD software is due to the tight integration of computer science research and expertise in the Group's development efforts. The requirements of NAMD users for new simulation capabilities drive advances in the Charm++ parallel runtime system, developed by the our university's Parallel Computing Laboratory, enabling future NAMD enhancements.

Simulation methods. The Group, now considered a leader in the field, was a late-comer to MD simulations when it started in 1989. Methodologically, the Group brought parallel computing and modern software technology to a field characterized by legacy code on conventional, serial computing platforms. But from the beginning, the Group took on a key new aim, simulations of membrane proteins in their natural environment, requiring 100,000-atom simulations.about twenty times larger than had been hitherto achieved. Starting with simulation of a 32,000 atom membrane patch [4], the Group achieved a highly-cited 106,000-atom landmark simulation of the aquaporin channel [7], and today routinely carries out 3-million-atom simulations of the ribosome in natural cellular environments [8]. The value of large simulations was questioned early on, but today many researchers employ NAMD and other simulation packages to carry out simulations of similar size. Spearheading large simulations makes the Group today a leader in computational cell biology targeting atomic level descriptions of the cell's multi-protein systems and organelles.

Extending simulation size required many times adopting new methodologies. An example is the need to describe long-range Coulomb interactions at a cost proportional to atom count. Other examples are the need for massively parallel computing, the need for the fastest possible program execution, and most recently, with the advent of 10 million atom simulations, the need for new data structures. Simulation set up and trajectory analysis requirements naturally led to parallel development of VMD and NAMD. Large-size simulations bring about the need to coarse-grained and reverse-coarse-grained simulations to avoid all-atom resolution where it is not required.

Anticipated Impact

The best evidence for the strong impact of the Group's technology is the large number of NIHfunded users of the programs VMD and NAMD. Combined, VMD and NAMD enable researchers to understand the molecular basis of diseases and to identify novel targets in pharmacology. NAMD is widely used by biomedical researchers at the world's supercomputer centers, being the most-used program in any discipline at some centers. In training workshops we encounter a large fraction of participants from experimental, e.g., crystallographic laboratories, often exceeding 50% of participants. VMD is a general, still unique, simultaneous access tool for sequence and structure data.

Some Key Activities in our Group

Our Group involves three Technical Research & Development areas (Fig. 1.4), seven Driving Biomedical Projects (Fig. 1.5), and ten Collaborations (Fig. 1.6), as well as Service (Fig. 1.7), Training, and Dissemination efforts. In addition to the above our group has strong research efforts in Photosynthesis and Animal Navigation, not covered here.

Technical Research & Development Projects

Interconnections between the three Technical Research & Development (TR&D) Projects.
Figure 1.4: Interconnections between the three Technical Research & Development (TR&D) Projects.

Figure 1.4 provides an overview of the three trainging research and development areas of our Group, highlighting also the many close links between them. At the core is the development of the sister programs NAMD and VMD (click for slides on NAMD and VMD). Even though the two programs can be, and often are, used independently, they integrate seamlessly and together form a unified and comprehensive simulation tool. The new Cell Biology Software development effort upholds the principle of close integration of our software, as shown in Fig. 1.4, adding four software packages that will assist modelers of cellular systems with a wide range of modeling tasks. MDFF will lead to a software suite, the Molecular Dynamics Flexible Fitting (MDFF) tool, for structure analysis of large assemblies through multimodal data from cryo-EM as well as low resolution X-ray crystallography and predicted structures (click for slides on MDFF). MEM seeks to offer the Membrane Environment Modeler software for modeling, simulation, and analysis of membrane processes. BD develops the Brownian Mover software suite for simulating the Brownian dynamics of biomolecules on μm length and ms-to-s time scales, e.g., for DNA-translocation through nanopore sensors (click for slides on BD ). Finally, CELLS will furnish a program package, the Lattice Microbes tool, that simulates whole cell behavior over the biologically relevant timescales of a cell cycle, accounting for transport processes and experimentally resolved inner-cell geometry (click for slides on Cell Biology).

Overview of the Driving Biomedical Projects
Figure 1.5: Overview of the Driving Biomedical Projects

Driving Biomedical Projects

Ribosome. Continuing our past studies of ribosome structure and function [8-16], we seek to solve structures of the bacterial ribosome docking to a protein chaperone called a trigger factor. The structure of the complex is to be solved employing new MDFF features such as tools dealing with flexible regions of an EM map. By using structure predictions as starting points for MDFF simulations, an innovative feature in the future MDFF suite developed by us, the Group also seeks to resolve structures of eukaryotic ribosome systems from yeast and Drosophila melanogaster. (Click for slides on Ribosome.)

Blood Coagulation Factors. The goal of this project is to describe in atomic detail how biological membranes control the binding and activity of blood coagulation proteins by dynamically changing their lipid compositions, and to characterize specific lipid-protein interactions and binding sites on the proteins that might serve as potential novel drug targets.

Whole Cell Behavior. The Group will investigate physiological processes at the cellular level with leading experimental researchers. Stochastic effects that result in cell-to-cell differences will be modeled to understand how pathogens use persistence to evade host immunity. Simulating large biochemical reaction networks will drive the development of our new Whole Cell Simulation software. Computational models of small eukaryotic cells and cell division in bacteria will require GPU acceleration. The whole-cell studies will be complemented by MD simulations at the organelle scale, namely of the chromatophore in purple bacteria, a simple bioenergetic pseudo-organelle. (Click for slides on Whole Cell Behavior.)

Biosensors. The Group will investigate the potential of a DNA nanopore sensor for sequencing human DNA at ultra-low cost. The sensor will be based on the bacterial membrane protein MspA [17, 18]. The Group will also work on increasing the fidelity of solid-state nanopore sensors through investigation of a new kind of graphene-based nanopore [19-21], offering ultimate resolution in detecting DNA base pairs [22]. (Click for slides on Biosensors .)

Viral Infection Process. The effectiveness of antiviral drugs is continually challenged by the emergence of new drug-resistant strains [23, 24]. An emerging opportunity to develop new types of drugs is through inhibition of virus cell entry [25-28]. The molecular mechanisms of the infection process for a model animal virus, poliovirus, and HIV will be studied. (Click for slides on Viral Infection Process.)

Integrin. Integrins are receptors on the cell surface, linking the cell to its surrounding environment. Due to their broad biological and therapeutic significance, integrins have been avidly investigated [29, 30]. Jointly with leading experimentalists, we seek to determine the molecular basis of integrin bidirectional (outside-in and inside-out) transmembrane signal transduction. (Click for slides on Integrin.)

Membrane Transporters. Membrane transporters mediate key processes in living cells such as termination of neural signals in the central nervous system, absorption of nutrients in the digestive tract, secretion of waste materials and ions in the kidneys, and development of drug resistance in cancer cells. Conformational changes of various forms and magnitudes, ranging from localized, gate-like motions to large-scale, global structural transitions, are at the heart of the function of membrane transporters. Characterizing these conformational changes has proven extremely challenging using experimental techniques. MD simulations offer an alternative means to resolve the conformational changes.

Collaborations

The Group is engaged in many collaborations with leading scientists across the US and the world.

Collaborations completed during 2007-2011 are listed here.
Our collaborations are ongoing and the group is engaged in the collaborations shown in Table 1.0. Three of the collaborations are depicted in Fig. 1.6 and described below.

TCBG Service Collaborations
Table 1.0: TCBG service collaborations

In our collaboration with the group of Barbara Seaton at Boston U., we are investigating the recognition of identifying hemagglutins on the surface of influenza A virus by lung surfactant collectin proteins, a component of the human immune system. Growing evidence suggests that evasion of collectin recognition is a factor in the severity of pandemic influenza strains. By uncovering the molecular mechanism of hemagglutin binding to collectins, we hope to exploit innate, collectin-mediated immune responses to develop new therapeutic approaches to fight against new or re-emerging strains of influenza. Another of our collaborations deals with the estrogen receptor, which is a ligand-induced transcription factor that plays a prominent role in numerous physiological and disease states. The Group is working to characterize the influence of ligand structure on estrogen receptor pharmacology, ultimately guiding the drug design efforts of our collaborators, John Katzenellenbogen (UIUC) and Kendall Nettles (Scripps-Florida). Our collaboration with Axel Brunger at Stanford U. deals with SNARE proteins, which play a vital role in the process of synaptic vesicle fusion. The Group will investigate the regulation and function of SNAREs during fusion by characterizing SNARE interactions with synaptotagmin and complexin, which are involved in calcium-mediated exocytosis. Other collaborations include work on protein folding, which is related to many neurological diseases, investigation into how editing domains in aminoacyl-tRNA synthetases prevent errors in translation, and characterization of how mutations in ankyrin proteins, which form the skeleton of red blood cells, can lead to hereditary anemia in humans.

Service Collaborations
Figure 1.6: Three of the ten service collaborations: anti-viral lung surfactant (with B. A. Seaton, Boston U.), the estrogen receptor (with K. Nettles, Scripps-Florida & J. Katzenellenbogen, UIUC), and SNARE complexes (with A. T. Brunger, Stanford U.).

Service

Four major components of Service by the Group Figure 1.7: Four major components of Service by the Group

The Group offers the four types of services shown in Fig. 1.7. First, it operates an advanced computational facility for visitors, collaborators, and its own personnel; the facility is geared, in particular, to handling and analyzing large trajectory data as they arise from petascale simulations. Second, the Group runs a visitor program offering office space and access to its computational laboratory as well as expertise. Third, the Group organizes support for NAMD and VMD users, a key activity that involves to an important degree the facilitation of community support. Lastly, the Group makes its personnel available for consultation regarding equipping and maintaining molecular modeling laboratories. (Click for slides on Service.)

Training

The Group's training program has provided direct training to 952 scientists since 2003, through a variety of Group-organized or collaborative workshops. Group-organized workshops include computational biophysics workshops, specialty workshops on computing topics, online workshops, e.g., on membrane proteins, and in-residence workshops, held at local and extramural locations. Evaluation results for Group workshops are consistently high. For example, 93% of participants at the November 2007 workshop at NIH's Bethesda campus and 100% of participants at the May 2011 workshop at the National Resource for Biomedical Supercomputing in Pittsburgh indicated that the workshop improved both the conceptual understanding and practical research skills of the participants. Other institutions have used Group faculty and training materials in their own workshop events, and via these 'collaborative workshops' the Group reached 157 further trainees. Group workshops have served as a focal point for development of new training materials, with ten tutorials providing over 360 pages of new content added since 2007 to over 600 already existing tutorial pages. All training materials are posted online to disseminate self-training opportunities to the biomedical community. (Click for slides on Training.)

Dissemination

The Group pursues its dissemination activities via multiple channels: website, publications, lectures and other means. The Group's main channel for dissemination, its website, has been highly successful, drawing 3.8 million unique visitors, resulting in 15 terabytes of information transfer from 2007 to 2011. Visitors to the Group website are drawn to a variety of resources provided at the Group website. In 2010, for example, the VMD home page drew 316,000 and the NAMD home page 172,000 visitors, while gallery pages of images, movies and brochures drew 33,000 visitors; 22,000 publications were downloaded from the Group's publication archive during that time. From 2007 to 2011, the Group produced 205 publications; the respective citation counts are high: Group publications from 1990 to 2011 were cited 29,000 times. Other dissemination activities from 2007 to 2011 include 340 lectures, 46 posters, and 183 instances of media coverage. The brochure Highlights 2006-2011 covers 87 research highlights, written by the Group staff on at least a monthly schedule.

For a discussion of early technological and scientific strides by the Resource, see the article Parallel Molecular Dynamics, 1988-2010.

References

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