Quantum mechanics (QM) is crucial to investigate subatomic mechanisms that occur in biology. However, studying entire biomolecular systems quantum mechanically is computationally prohibitive. Traditionally, NAMD employs classical molecular mechanics (MM) to determine the movement of a molecule, solving Newton's equations of motion and treating atoms as spheres and bonds as springs. Combining both approaches, hybrid QM/MM methods employ the quantum mechanics formalism to key regions of the biological system, while using molecular mechanics approach to include the effects of the surrounding area. NAMD's new QM/MM interface can be combined with many molecular dynamics protocols, such as enhanced sampling and free energy calculations. This combination was crucial in the investigation, appearing in Nature Methods, of the mechanism that sets the genetic code, when DNA's three-letter code is translated to protein's amino acid residues. Uniting a large set of tools in VMD, QwikMD, and NAMD, the QM/MM simulations revealed the subatomic details of this mechanism, providing an unique view for this essential step of life. Read more in Nature Methods, or from our QM/MM website.

Bacteria are remarkable at tailoring their bioenergetic machineries to adapt to and thrive in diverse and ever-changing environments. A critical metabolic task is the efficient extraction of energy from food. Similar to us, many bacteria pass electrons to oxygen or other acceptors with the help of membrane-bound enzymes, and in doing so, they move protons across their membrane, thus generating a transmembrane voltage (much like a battery) that can be used for ATP synthesis. Typically, one enzyme passes an electron to its downstream enzyme via random collisions. However, sometimes these enzymes can form a supercomplex that positions the enzymes very close to each other and with the right pose for faster electron transfer and therefore more efficient energy conversion. In a recent paper reporting a three-way collaboration between biochemists, experimental structural biologists, and the Center researchers, the structure of one such supercomplex (termed Alternative complex III) was determined at an atomic resolution through a combination of cryoEM and advanced molecular modeling and simulation tools performed with NAMD and VMD. Read more about this study in Nature.

Staph infections are caused by bacteria commonly found on the skin of healthy individuals, where they can only cause relatively minor skin problems. However, when staph bacteria enter a person's bloodstream, they can travel to locations deep within the body causing infections that are often hard to treat. Not surprisingly, staph infections are the leading cause of healthcare-related, so called nosocomial infections. Particularly vulnerable areas are medical devices such as artificial joints or cardiac pacemakers, where the bacteria strongly stick to through formation of biofilms. Central to biofilm formation is an unusually tight interaction between microbial surface proteins called adhesins and the extracellular components of the host cells. In a recent report in Science , researchers used a combination of atomic force microscopy and GPU-accelerated molecular dynamics simulations using QwikMD and NAMD , to explore how the connection between adhesin and its target fibrinogen peptide can withstand huge forces greater than 2 nano-Newtons (see also Perspective in Science. ). The geometry and molecular details of the interaction ensures that, when pulled, the load is distributed over many hydrogen bonds all of which need to be broken at once before separating the bacterium from the surface of the host cell (see video on YouTube ). The unexpected, new mechanism, expands our understanding of why pathogen adhesion is so resilient and open new avenues for an intelligent design of antimicrobial therapies through development of anti-adhesion drugs. Read more in Science.

From bacteria to mammals, different phospholipid species are segregated between the inner and outer leaflets of the cellular membrane by ATP-dependent lipid transporters. Disruption of this asymmetry by ATP-independent phospholipid scrambling is a key step in cellular signaling, e.g., in apoptosis and in blood coagulation. Using molecular dynamics simulations with NAMD coupled with experimental assays, a recent collaborative study with H. Criss Hartzell (Emory University) published in eLife shows how a hydrophilic track formed on the surface of scramblases serves as the pathway for both lipid and ion translocations and how Ca²⁺ controls the open/closed transition of the track. The results of the simulations were used to successfully engineer scramblase activity in a homologous Ca²⁺ activated ion channel member of the family. This work provides a microscopic view of how lipids and other lipophilic molecules can permeate specialized proteins to travel between the two leaflets of the cellular membrane. Further details of the study can be found here.

Deciphering the nuts and bolts of the how the brain works is crucial for understanding human psychology and behaviors developing novel and more effective treatments for neurological diseases. The human brain's function relies on the transmission of electric signals from one neuron to another through the synapse, a delicate process mediated by diffusion of neurotransmitter molecules released from the presynaptic cell that bind their specific receptor on the postsynaptic cell. In a recent collaborative study, performed with the experimental lab of Eric Gouaux (Vollum Institute), one of the key receptors, known as the AMPA receptor, was characterized in its three major functional states: closed, desensitized and active (see Figure 1). The study has uncovered the long-sought structures for the active and desensitized states of this protein for the first time (using cryo-EM) after decades of research. These structures provide vital information as to how this ion channel receptor converts the chemical signal of the neurotransmitter to a temporally controlled excitation profile in the postsynaptic neuron. The method of MDFF developed by the Center was used for refinement of the structure, and NAMD simulations together with VMD visualization were used to characterize the open state of the channel.

Proteins play major mechanical roles in a cell. Mechanical properties of proteins can be substantially modulated by slight changes in their amino acid composition, an ability essential to bacterial cells, which use protein repeats with small modifications to tune their mechanical strength, and thus their functional properties. A prime example of the role of biomechanics in the cell is found in symbiont gut bacteria who need to hold to their food source in such turbulent environments as the rumen of the cow. Proteins evolved for this purpose are known actually to be among the strongest mechanical biomolecules. Key to the process are molecular tentacles, so-called cellulosomes, on the surface of symbiotic bacteria. The cellulosomes develop a tight grasp on and then effective cleavage of hardy cellulose fibers of the grass. In a joint experimental-computational study researchers investigated the mechanical properties of cohesin, a major cellulosome component, under force. Using NAMD, all-atom steered molecular dynamics (SMD) simulations on homology models offered insight into the process of cohesin unfolding under force. Based on the differences among the individual force propagation pathways and their associated correlation communities, the researchers were capable of designing protein mutants to tune the mechanical stability of the weakest cohesin. The proposed mutants were tested with high-throughput atomic force microscopy experiment revealing that in one case a single alanine to glycine point mutation suffices to more than double the mechanical stability. Read more about our cellulosome research here.