TCB Highlights of our Work

Eyes of Plants

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The ability to sense light is crucial for both plants and animals; animals use their vision to navigate and interact with their surroundings, whereas plants grow toward light to optimize photosynthesis. One of the most important photosensors in plants relies on tiny molecular switches known as LOV domains. When light strikes a LOV domain, it causes the formation of a single chemical bond; the unique structure of the LOV domain converts this subtle change into a protein unfolding event that triggers signaling. The mechanism through which LOV domains amplify bond formation into large-scale molecular motion is of great interest both for designing light-activated proteins for synthetic biology applications, and as a model for understanding the harder-to-study molecular switches that govern most of the functions of living cells. As reported recently, researchers used a series of long-timescale molecular dynamics simulations to show the locations of molecular levers that allow light-induced bond formation to rearrange the entire structure of the LOV domain. The simulations highlighted two main paths of information flow from the heart of the photoreceptor to the surface of the protein, giving unprecedented insight into the function of this light-activated molecular switch. More information is available on the biological photoreceptors website.

Good News for the Easter Bunny

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Rabbit hemorrhagic disease is extremely contagious and associated with liver necrosis, hemorrhaging, and high mortality in adult rabbits. First described in China in 1984, within a few years, rabbit hemorrhagic disease spread to large parts of the world and today threatens the rabbit industry and related ecology. The disease is caused by a virus, aptly named rabbit hemorrhagic disease virus. As reported recently, a group of experimental and computational researchers combining crystallography, electron microscopy and data-guided molecular dynamics simulations utilizing NAMD determined an atomic model of the capsid, namely the protein shell that surrounds the genetic material of the virus. The capsid simulations involved 10 million atoms and have become feasible only through Blue Waters, a brand new petascale supercomputer. The atomic model, analyzed by means of VMD, recently adapted to studies of very large structures, resolves the structural framework that furnishes both mechanical protection to the viral genes as well as a quick release mechanism after a virus enters a host cell. Researchers can use the detailed knowledge of the capsid structure to develop vaccines against rabbit hemorrhagic disease. More information is available on our virus website and in a news story.

Molecular Tortoise

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For newly made membrane proteins, getting to their final destination in the membrane requires another protein, the channel SecY, to provide a pathway (see the Sept. 2007 and Feb. 2011 highlights). But just knowing the route is not enough, because SecY presents the nascent protein with a choice: insert into the membrane or cross the channel to the watery exterior. How the nascent protein comes to a decision has long been a point of uncertainty, although it has been presumed to be driven by purely energetic considerations, i.e., the protein goes to the environment it ultimately prefers. Now, recent simulations and free-energy calculations spanning time scales from nanoseconds all the way to seconds have revealed that how long the nascent protein deliberates in the channel is just as great a factor in its final location as how favorable it is there. It was found that the longer the protein takes to decide, the more likely it is to choose the membrane, proving that, at least for membrane insertion, slow and steady wins out. More information can be found on the protein translocation website.

Hot Quantum Effects

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Quantum mechanics rules all natural processes, but is manifested most strongly when acting on the lightest particles, namely the well-known electrons. To study quantum effects physicists routinely resort to very low temperature, that of liquid helium. Amazingly, living systems seem to exploit quantum effects for their benefit, but do so at temperatures typical for life, namely around room temperature or warmer. A particularly important case is photosynthetic light harvesting where so-called quantum coherence plays a critical role when electrons in assemblies of chlorophylls become excited by sun light and the excitation energy is harvested by utilizing it to charge photosynthetic membranes. In order to understand how photosynthesis can exploit room temperature quantum effects one needs to know how the temperatures, which are much higher than those in the physics laboratories where liquid helium is employed for cooling, affect electron behavior. The knowledge can be gained by so-called dissipative quantum mechanical descriptions, but the needed computer calculations are extremely demanding. To address this demand, researchers have developed the software PHI that uses the power of parallel computers, as described in a recent report. PHI has already been used to understand how many chlorophyll molecules act together to absorb sunlight among themselves and let the excitation migrate between chlorophylls to so-called reaction centers where the excitation energy is converted into a membrane potential. The overall light harvesting process has been described in various reports (1, 2, 3) and in a review (4). The PHI software can be obtained from our web site. More information on PHI is available here.

How Membranes Curve

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Olga Svinarski and VMD

The cells of higher life forms, so-called eukaryotic cells, are subdivided through many internal membranes made of lipid bilayers. The internal membranes assume numerous shapes, like spheres, tubes or parallel sheets. Outside of cells, biological membranes adopt usually flat shapes and the question arises, how do eukaryotic cells sculpt their inner membranes? The question of flat membrane sculpting is particularly interesting also as mature cells constantly produce new membrane shapes, for example spherical vesicles filled with certain biomolecules destined for release into the extracellular space, a process called exocytosis. The cell has many mechanisms available for sculpting its membranes, one of them relying on proteins called BAR domains that act from the surface of lipid bilayers. Molecular modeling with NAMD and VMD has provided valuable views of BAR domains at work in case of the so-called N-BAR family (see the earlier highlights Protein Teamwork, Jun 2009 and Proteins Sculpting Cell Interior, Sep 2008). Researchers report now an extension of the earlier studies to the F-BAR domain family of membrane sculpting proteins. The new modeling work is particularly exciting as it can be directly compared to electron microscopy images of membrane tubes sculpted from flat membranes in experiments done outside of cells. The new studies reveal how F-BAR domains sculpt tubular membranes through the shape of dimerized domains and through F-BAR domains not acting individually, but as an army of F-BAR domains adopting an ordered formation on one side of the membrane. More on our F-BAR domain web page.

Everybody Can Fold Proteins

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Every living cell relies on proteins to carry out its functional tasks; every protein needs to assume a proper shape in order to be operational for these tasks. How a protein, composed of a particular sequence of amino acids, could find its way to a proper shape is a fundamental, yet mysterious biological process. Researchers have sought to unravel atomistic details of protein folding processes through computer simulations, but modeling such processes is computationally demanding. It was only recently that some researchers have been able to observe in some case how proteins fold, but needed for the purpose the fastest computers available today. One of these computers is Anton, the expensive special-purpose supercomputer available essentially only to a single research group. Is there an affordable way to simulate protein folding? One solution could be coarse-grained methods. These methods save tremendous computational effort by replacing computational models that include all atomistic detail. However, the simplified models need to include a sufficiently accurate description of proteins for modeling folding processes. As reported recently, researchers have overcome the challenge by combining atomistic and coarse-grained descriptions. The new method is fast enough to follow movements of proteins long enough to see them fold, while requiring only readily available computer powers. The new method allowed researchers to analyze complete folding events for seven proteins, including a protein, called α3D (see movie, 11.5 M), that is one of the largest proteins ever folded computationally. More on our hybrid-resolution model website.

Cryptic Light Receptor

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Animals and plants, together with other life forms, possess internal clocks that attune them to the daily rhythm on Earth. A sign of such clocks is jet lag, the discomfort experienced by humans when due to travel across several time zones our internal clocks need to be reset to the new time zone. Feed-back to local day light assists the resetting and a key light receptor serving the purpose is a protein called cryptochrome. The name was chosen as the receptor hid for a long time from the instruments of researchers, but today the name seems still appropriate as the physical mechanism of the receptor is shrouded in mystery and subject to dispute. Adding to the mystery is an apparent second role of cryptochrome, namely that of a sensor for the Earth' magnetic field, which helps migratory birds and many other animals in long-range navigation (see our magnetoreception page). The biological function of cryptochrome supposedly arises from a photoactivation reaction involving electron transfer, but the reaction pathway is difficult to resolve experimentally as the best available method, time-resolved spectroscopy, cannot identify unequivocally the photoproducts produced through cryptochrome light absorption. Experimentalists hate to admit the calamity, but likely the only way out are a combination of quantum-chemical and classical molecular dynamics calculations. Such calculations were recently performed and the results reported. The calculations demonstrate that after absorption an electron is transferred inside cryptochrome, the new state becomes stabilized through proton transfer and decays back to the protein's resting state on time scales allowing the protein, in principle, to act as a light as well as magnetic sensor. More details can be found on our cryptochrome webpage.

Fighting the Flu using Computation

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Did you get your flu shot this year? Influenza is a leading cause of preventable death in the industrialized world, representing hundreds of billions of dollars in healthcare expenditures and loss of economic production. While the yearly influenza vaccination is nearly 90% effective at limiting infections in populations less than 65 years of age, there is insufficient evidence regarding the effectiveness of the flu shot for the elderly population, whose immune systems may not mount an adequate antibody response to vaccination. Beyond vaccination, front-line therapies such as the neuraminidase inhibitors Tamiflu and Relenza have proven to be of limited effectiveness due to the evolution of drug-resistant influenza mutants. Therefore, a need exists for the development of new therapies to circumvent these resistance mechanisms. Computational biologists employing NAMD and VMD used molecular simulations to uncover the key role that water plays in mediating how well antiviral drugs can bind to proteins of the influenza virus. This investigation, reported recently, reveals that amino-acid mutations responsible for drug resistance act by reshaping the local electric field and also by permitting infiltration of water within the otherwise hydrophobic drug binding pocket. These mutations thus induce drug resistance in much the same way as inverting the polarity of a magnet can repel rather than attract. These findings are expected to help guide the design of novel drugs with increased antiviral efficacy. Additional details about this study can be found here.

Viral Ion Channel

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see also movie1, 3.3MB
and movie2, 4.4MB

All living systems contain proteins whose job is to move ions across a lipid membrane. Even viruses encode ion transport proteins, which they need to complete their lifecycle and release themselves from infected cells. Such proteins, called viroporins, usually consist of small subunits of one or two helices that can self-assemble in a lipid bilayer into a pore-like structure. Although in some cases, the resulting structures resemble the well-ordered, selective ion channels in higher organisms, often they take on a more disordered character, forming pores with variable numbers of subunits, which adapt their structure and behavior to the environment in which they find themselves. This inherent flexibility and disorder makes it very difficult to produce high-resolution crystal structures of viroporins, which is unfortunate, since they could offer attractive drug targets for new antiviral therapies. Computational modelling and molecular dynamics simulations can help fill in the gaps in our structural knowledge of viroporins, and provide plausible 3-D models for visualization and drug design. In a recent publication, scientists published models of the p7 viroporin found in Hepatitis C virus. MD simulations of these models revealed that p7 can form stable pores with 4 to 7 subunits, with a bias towards 6 or 7 subunits, and that the p7 oligomers are highly flexible in adapting to different membrane thicknesses. These simulations also suggested that specific amino acids in certain places in the structure could play a role in controlling the ion permeability of p7. More details can be found on our p7 website.

Engineering Atomic Detail

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Nanoengineering permits the manufacturing of sensors of unprecedented accuracy to detect biomolecules at very low concentrations as they arise, for example, as signals in living cells. In an important type of cellular signaling, proteins are modified through addition of a phosphate group by other proteins, so-called kinases. Kinases are involved in various types of cancers; therefore, bioengineers seek to develop a nanosensor to detect kinase activity. As described in a recent report, they grafted short peptides, containing a tyrosine amino acid, on nanometer scale gold surfaces. Phosphate groups are negatively charged, and as the groups are transferred from the kinases to the peptide�s tyrosine, the overall charge of the grafted peptides increase. Bioengineers detected then the phosphorylated peptides by applying electrical fields that would drive the charged phosphate group towards the surface or away from it, depending on the voltage polarity; the resulting conformational change of peptides can be recognized by shining light on the nanosensors as optical properties of molecules near metal surfaces are amplified. In order to make the nanodevice really work, the bioengineers needed to optimize the peptide sequence, know how phosphorylation and voltages alter the near-surface conformation of the peptides and how to interpret the measured optical signals. In other words, they needed a microscopic view of the nanodevice! Such view was achieved through molecular dynamics simulations using NAMD and VMD following in the footsteps of similar earlier uses of such simulations as a computational microscope (see Diet and DNA, Sep 2011; Bumpy DNA, Feb 2009; Stretchable DNA, Nov 2005). The combination of nanoengineering and molecular dynamics simulations produced indeed a satisfactory kinase sensor prototype. For more information, visit our kinase sensor website.

Shield Against Influenza

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The fall flu season is coming. It is time to get your flu shot! Many people may still remember the influenza A H1N1 flu ("swine flu") pandemic of 2009, which caused 280,000 deaths worldwide. The best way to prevent the flu is to get vaccinated with a flu shot or use the flu nasal spray vaccine. However, rapid evolution of the flu virus constantly requires new vaccines. Fortunately, the immune system has several defensive mechanisms in the lung to clear inhaled pathogens. One of these mechanisms involves surfactant proteins which induce aggregation of viral particles and, thereby, prevent infection, serving as a front-line host defense. Recently, researchers found that surfactant protein D (SP-D) from pigs exhibits particularly strong inhibitory activity, more so that human SP-D. This discovery leads researchers to investigate SP-D structure-related antiviral activity. In a recent experimental-simulation study, crystallographic analysis of pig and human SP-D showed that a loop involved in viral binding on pig SP-D is longer than the respective loop on human SP-D; molecular dynamics simulation revealed that the longer loop of pig SP-D has higher flexibility than that of human SP-D, suggesting that the flexible loop region could facilitate strong binding of SP-D to virus. Based on this finding, one can develop new nasal spray anti-flu protection through other structural modification of human lung surfactant proteins. More on our lung surfactant protein website.

Electrons Help the Nose

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see also video, 224MB

Hearing, sight, touch, taste, and smell are the five basic senses that link animals and humans to their habitat. In particular, smell, or olfaction, endows animals and people with the ability to detect and distinguish different scents through volatile odorant compounds and, thus, provides a crucial ability to recognize food or evade predators. The five senses have been studied extensively and are believed to be well characterized, but remarkably the fundamental mechanism of olfaction is still debated. The mainstream explanation of smell is based on recognition of the odorant molecules through characteristics of their surface, e.g., shape, but certain experiments suggest that such recognition is complemented by recognition of vibrational modes. As recently reported, according to the latter suggestion, an olfactory receptor is activated by electron transfer assisted through odorant vibrational excitation. The hundreds to thousands of different olfactory receptors in an animal recognize odorants over a discriminant landscape with surface properties and vibrational frequencies as the two major dimensions. The analysis revealed a range of physical characteristics which olfactory receptors and odorants must obey for the vibrationally assisted electron transfer mechanism to function. More details are provided on our olfaction website.

Born to Control

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The ribosome functions as a cellular protein factory, synthesizing practically all the proteins in the cell based on blueprints read from DNA (see the April 2012 highlight and Dec. 2009 highlight). However, unlike an assembly line, the ribosome has no foreman directing it. Instead, regulation of protein synthesis is managed by a number of external, and internal, signals. For example, the protein TnaC halts its own synthesis in the ribosome to promote that of another protein (see the May 2010 highlight). Similarly, synthesis of the protein SecA, a translocase that aids in pushing newly made proteins across membranes, is controlled through the nascent protein SecM. Regulation of SecA levels is the only function of SecM, which is degraded as soon as it leaves the ribosome. It is the stalling of one ribosome by SecM that provides enough time for secA, which resides on the same messenger RNA as secM, to be translated by a second ribosome, thus upregulating SecA production. When enough SecA has been produced, it pulls on the portion of SecM outside the ribosome, relieving its stalled state. The critical interactions that cause stalling have now been identified through a combination of molecular dynamics and cryo-electron microscopy via MDFF and NAMD. As recently reported, these interactions form a relay connecting SecM in the exit tunnel to the ribosome's key catalytic center, preventing synthesis and thus explaining how SecM stalls inside "its" ribosome. Additionally, steered MD simulations revealed how SecA can cause the nascent SecM to become unstuck, by breaking those same interactions. More details are provided on our ribosome website.

Large Protein Folded Computationally

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Proteins are the biological workhorses in living cells. For example, they respond to external signals arriving at the cell surface or transport cargo, much larger than themselves, from one place to another in the cell. However, before a protein can carry out his job, it must first assume the proper shape. Proteins are long polymers of twenty different amino acids linked in a linear sequence; the latter is particular for each protein. It is still a mystery how a protein folds into the proper shape based on its sequence. Scientists hope that one day they can "watch" this folding process for any given protein. The dream has been realized, at least partially, through the use of computer simulation. After tackling the protein-folding problem already computationally for two small proteins (see May 2008 highlight and Nov 2009 highlight), researchers have now successfully visualized the complete folding process of a relatively large protein, the so-called λ-repessor (see movie, 7.8 MB). In fact, it is one of the largest proteins folded to date using a computer. As reported recently, simulations carried out with the program NAMD, as well as simulations carried out on a special purpose supercomputer, Anton, achieved to follow λ-repessor's folding movement for more than 0.0001 seconds, long enough to observe the protein assume its proper shape. More information is available on our protein folding website.

NAMD 2.9 Brings MDFF to the Desktop

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X-ray crystallography resolves the structures of the molecular machines in living cells at an atomic level of detail, but only in states that can be captured as crystals, which are often not functional states. Cryo-electron microscopy enables a more complete view of biomolecular conformational variability, but at lower resolution. The molecular dynamics flexible fitting (MDFF) method combines the atomic detail of crystallographic structures with lower-resolution cryo-electron microscopy to synthesize all-atom models of complex macromolecular aggregates such as the ribosome in multiple functional states. The 2.9 release of NAMD combines GPU acceleration of implicit solvent simulation, optimizations exploiting shared memory within a single machine, and a faster "lite" grid forces implementation to bring MDFF capability from the supercomputer to the desktop. VMD can connect to a running simulation to visually monitor the progress of the simulation or to interactively steer a molecule with either the mouse or a haptic (force-feedback) interface device. The convergence of methodology, software, and hardware advances thus opens what was once the domain of extremely expensive equipment to commodity computers.

NAMD 2.9 Goes Viral on Blue Waters

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Viruses reproduce by splicing their genetic material into a host cell, causing the cell to manufacture new viruses. This genetic material is protected outside of the host cell by a protein capsid, which disassembles inside a new cell to complete the infection process. Simulation of viral infection has progressed significantly since the first all-atom virus simulation was done with NAMD in 2006 and is one of the driving biomedical projects for the software. A new collaboration with the Pittsburgh Center for HIV Protein Interactions has applied molecular dynamics flexible fitting to construct the first all-atom structure of an HIV virus capsid in its tubular form (shown). This structure is now being simulated as one of six early science projects on the Blue Waters petascale supercomputer being installed at Illinois. These large-scale simulations are enabled by the 2.9 release of NAMD, which includes a new high-performance interface to the Cray Gemini network of Blue Waters. Smaller simulations may also leverage petascale computing through a new replica-exchange framework that supports parallel tempering and integrates with the collective variables module for umbrella sampling conformational free energy calculations. GPU acceleration enhancements include minimization and implicit solvent support as well as exploitation of shared memory, extending performance gains to the desktop.

VMD 1.9.1 Adds Fast Surface Display

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The surfaces of biomolecules are alive with activity, with surface shape and electrostatic interactions leading them to interact with each other. The recent VMD 1.9.1 release includes a new "QuickSurf" graphical representation for molecular surfaces that allows the dynamics of large biomolecules to be animated interactively for the first time. VMD 1.9.1 even enables surface representations for many-million atom complexes. QuickSurf uses fast algorithms, GPU computing techniques, and multi-core CPUs to achieve astonishing performance. The algorithms behind QuickSurf have been recently reported. VMD 1.9.1 adds many other new features including a new Force Field Toolkit (FFTK) plugin that assists researchers in development of CHARMM force field parameters, a new NetworkView plugin for mapping and displaying networks on 3-D molecular structures, an updated ViewChangeRender plugin for making sophisticated demonstrations and movies, and a new VMD remote control tool that allows VMD sessions to be controlled from wireless touch sensitive phones and tablet devices. For more on these and other new features of VMD see the VMD 1.9.1 release page.

The Protein Assembly Line

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The ribosome is the protein assembly line in all living cells. The building material for new proteins is supplied by RNA molecules, called tRNA. They enter and move through the ribosome, each adding a new amino acid to the nascent proteins according to the genetic sequence provided through so-called messenger RNA. During the tRNAs' translation through the ribosome, the ribosome itself is not static either. A ratcheting motion and other large scale motions can be observed. However, the exact tRNA and ribosome motion were not clear. Using images from cryo-electron microscopy, MDFF, a computational method based on NAMD, allows one to see the moving parts within the ribosome in great detail. MDFF (see the June 2008 highlight) already provided crucial and unique insights into different aspects of protein synthesis, such as translational arrest of the ribosome by a nascent chain or translocation of an emergent protein across a membrane. In the work reported recently, MDFF revealed the presence of previously unseen intermediate states of the ribosome and its bound tRNAs during the ratcheting motion. A thorough analysis of these states pictures the ribosome as a molecular machine using Brownian motion for its function. More on our ribosome website.

Quantum Physics in Bacteria

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Many bacteria use sunlight as an energy source. The energy gained from a solar ray absorbed by a molecule, however, lasts only for a very short time (a mere 0.000000001 seconds!) before it dissipates away and is lost. Within this short time, machinery in the bacterial cell must store the light energy in a longer-lasting form so that it can be used later. A series of reviews describes how bacteria exploit quantum physics to bottle the energy of sunlight for a sufficiently long time to fully utilize it. In a first review we introduce the light harvesting systems of bacteria and their key molecular components, in particular the role of chlorophylls. In a second review we describe how thousands of chlorophylls cooperate to transport the short lived energy of absorbed light to the centers where the energy is converted into a more stable form, namely that of a voltage difference across the bacterial cell wall. In a third review we explain how quantum physics enhances this process of energy transport in bacteria (see also our video). In a fourth review we describe how the individual components of this system come together into their overall organization. More information about the machinery and process of photosynthesis can be found here and about the physics of energy transfer in photosynthesis here.

Secondary Pores in Potassium Channels

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Voltage-gated ion channels, present in the membrane of excitable cells, control the ionic concentrations of the cellular environment by maintaining a potential difference of -100 mV between inside and outside of the cell membrane. Voltage-sensing occurs through distinct protein modules, known as voltage-sensor domains, four of which surround the main conduction pathway in potassium channels. Mutation of a certain amino acid on the voltage sensor domain turns these protein modules into cation channels, known as omega pores, which allow conduction of ions only when the main pathway is closed. Omega pores closely resemble the long-sought voltage-gated proton channels, which were recently identified to follow the same voltage-sensing mechanism as voltage-gated cation channels. In a recent report, researchers have visualized the twisted permeation pathway of the ions through omega pores using the molecular dynamics program NAMD. The simulations revealed a narrow constriction region lined by negatively charged amino acids, acting as a selectivity filter that prefers passage of positively charged ions through the pore. For more detail, see our potassium channel website .

Light-driven Magnetic Compass

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Courtesy of Vita Solovyeva

Creatures as varied as mammals, fishes, insects, reptiles, and birds have an intriguing 'sixth' sense that allows them to navigate in the Earth's magnetic field. Despite decades of study, the physical basis of this sense remains elusive. A likely mechanism is furnished by magnetic field sensitive reactions occurring in the retina of animal eyes. A decade ago it was suggested (see our magnetoreception page) that the photoreceptor cryptochrome, arising in the retina, endows birds with magnetoreceptive abilities. The hypothesis gained support during the last years, after it had been shown that the protein exhibits properties required for an animal magnetoreceptor to operate properly. (see prior highlights on A Compass in the Eye, July 2010; on Where's North, Ask Superoxide, July 2009; and on Animal Magnetic Sense Shared by Plant, April 2007). However, the biophysical mechanism of cryptochrome activation and signaling is still poorly understood. A recent study proposed a theoretical analysis method for identifying cryptochrome's signaling reactions involving comparison of measured and calculated reaction kinetics. Application of the method suggest a light-driven reaction cycle which combines electronic excitation with electron and proton transfer reactions in the protein. More details on cryptochrome functioning as a light-driven magnetic compass can be found on our cryptochrome webpage .

Epigenetic Key

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Genes encoded in DNA sequence give a complete set of instructions for the development of a new organism. However, an organism, like the human body, develops also over a life time adapting to environment and experience, for example to diet and exercise. Recently, researchers found that such factors act through so-called epigenetic mechanisms that alter an organism's development without altering DNA sequence. One such mechanism involves DNA methylation, a chemical modification of one of the four bases of DNA, cytosine, that replaces a hydrogen atom with a methyl group. There are several ways that DNA methylation exerts its biological function, bringing about a long-time adaptation of an organism to its environment, in some cases even across generations. Our previous experimental and computational studies (see Sep 2011 and Feb 2009 highlights) indicated that methylation changes mechanical properties of DNA which can affect gene expression. DNA methylation can also inhibit gene expression by impeding proteins that control the translation of DNA sequence into protein synthesis. One mechanism involves DNA methylation sites recruiting genetic control proteins that inhibit DNA expression through their local presence. In a recent study, computational biologists performed MD simulations with NAMD along with quantum chemistry calculations to determine recognition of methylated DNA by proteins. The simulations revealed how a certain genetic control protein, called methyl-CpG binding domain protein, acts in tandem with methylated DNA like a key and a lock, methylated DNA and protein perfectly matching each other. More details can be found on our methylated DNA website.