Cellular processes are governed by the intricate coordination and dynamics of biological macromolecules called proteins and nucleic acids. These do not act in isolation but rather interact with each other and assemble to form cellular complexes. Understanding the structures of complexes can be an important step not only in understanding basic cell biology but also disease, as such complexes are also formed between the proteins of invading pathogens like viruses and the host cell proteins. Indeed, to determine how a virus functions, knowledge is needed not only about the molecular arrangement of its own proteins but also about their interactions with the host cell over the course of the viral life cycle. Particularly interesting is the entry process, the earliest stage of infection in the cycle, when the virus comes into first contact with the host cell and introduces viral material into the cell. The goal of our project is to gain a structural view of the entry process in one of the largest and most complex families of viruses that infect humans - the Herpesviruses. The severity of conditions caused by these viruses ranges from cold sores, genital ulcers, and blisters to blindness and life-threatening conditions including fatal encephalitis, meningitis and cancer. This family constitutes a major public health concern due to their worldwide prevalence, ease of spread, and severity of the associated symptoms. To achieve this, we propose a multi-disciplinary approach that integrates computational and experimental methods. The field that aids this project is Structural Biology. It provides 'pictures' of macromolecular complexes and their components through the use of experimental techniques such as X-ray crystallography and nuclear magnetic resonance, each of which has its own limitations to what it can accomplish, depending on the size and purity of sample under investigation, the conditions in which its prepared, and the homogeneity of the complex it contains. In the last decade, cryo electron microscopy and tomography have also become important techniques for observing biological complexes. With these techniques, samples are rapidly frozen using cryogenic liquids and then bombarded with electrons, yielding many images of the 2-dimensional sample that can be combined into a clearer 3-dimensional picture. In tomography, such pictures can provide the overall organization of cells and tissues, and can capture pathogens during cell invasion. They contain many different macromolecular complexes that can be detected in their native environment. Though these techniques have led to many interesting discoveries, here too there are limitations, typically not resulting in near-atomic pictures. In this project, we will study the entry process in human herpesviruses. To this end, we will develop a computational approach that pulls together information from a variety of experimental techniques to construct a clearer and more complete description of structures of complexes imaged initially by cryo electron tomography. The method will have the capability of incorporating information about which protein interacts with which (or how close they are to each other). Such information could come from a variety of techniques, often grouped under the name 'proteomics'. Together, we will fit all the different pieces of information like a jigsaw puzzle, creating a higher resolution picture of the visualised complexes. Obtaining the structures of selected complexes (formed between the proteins placed on the envelope of the virus and between them and their interacting proteins from the host cell) will represent a major advance in our understanding of the molecular and mechanistic details of herpesvirus pathogenesis. This will allow us to improve current models of the entry process, a crucial step towards identifying drug targets. Our novel approach will be applicable to many viral systems and will open the door for similar studies on other pathogens.

Day to day life is increasingly reliant on electricity to support transport and communications in addition to the storage and preparation of food. This situation reflects rapid scientific developments since Alessandro Volta built the first battery just over 200 years ago. However electricity has been essential to humans, and indeed all forms of cellular life, ever since they have existed. This electricity arises from the electron transport chains underpinning the storage of solar energy in sugars during photosynthesis and the harnessing of the energy in sugars for cellular function, reproduction and motility during respiration. Specially designed proteins support electron transport during photosynthesis and respiration. Many of these proteins contain metal ions positioned at regular intervals within a polymer made of amino acids and we can immediately see parallels to the structures of the much larger cables and wires that move electrons in our mobile phones, toasters etc. The properties determining the flow of electrons through cables and wires are well established. However, the means by which a particular amino acid structure defines the rate of electron transfer within and between such proteins when dissolved in water is less well understood. Here we propose to provide insight into these mechanisms through a combination of computational and experimental methods. The subject of our study is an iron-containing protein, whose three-dimensional structure has been solved only a few months ago. This protein is a representative of a large family of structurally related, but functionally distinct, proteins that has been recognised only recently. These proteins allow microbes to colonise diverse and apparently inhospitable environments. They contribute to the operation of some microbial fuel-cells and to the virulence of numerous microbes capable of infecting humans and animals. By resolving the molecular details underpinning electron transport through these proteins we will provide fundamental insight into a wide-spread and important mechanism of biological electron transport. Some of the computational methods are already available and some of them need to be developed during the research programme. The new methodologies will be made available to other scientists for studying other proteins of interest. The knowledge gained will also provide the framework for developing proteins with bespoke electrical properties for use as molecular nano-wires in bioelectronic engineering.

Different sequences of atoms give molecules with distinct shapes. This shape is key to a molecule's properties, e.g., its biological effect when binding proteins. Conventionally, the atomic sequence of a molecule is fixed. This proposal, however, investigates molecules that break free from this dogma. 'Shapeshifting' molecules adapt their atomic sequences to match their surroundings. During this Early Career Fellowship, the project team and I will establish methods to control shapeshifting molecules. We will pioneer their applications in catalysis, drugs, and plastics. We expect to discover rare properties, such as plastics made from molecular networks that spontaneously tangle and untangle, making them uniquely strong and flexible. We will also answer open questions about how shapeshifting molecules adapt when they interact with other molecules, quantifying changes in their structures. This knowledge will allow us to make shapeshifting molecules that mould themselves to match complex biological targets implicated in disease. By the end of the grant, we will have shown how shapeshifting molecules differ from conventional materials. We will have also demonstrated the first of their many possible applications in biology and soft materials. These fundamental, chemical advances establish a new research area that will have broad impacts in biochemistry, materials physics and engineering.

The quantum world is innately parallel. Quantum objects may exist in many places at the same time and in general have a superposition of attributes that would be mutually exclusive for an object on the everyday classical scale. In 1982 Richard Feynman suggested that one might attempt to use this parallelism to speed up computation and in 1982 Peter Shor discovered an algorithm that could, theoretically, make use of it in a calculation. Since these early theoretical works, there has been a dramatic effort in the theory of quantum computation while at the same time trying to find a physical system where these ideas could be realized. Taking the queue from the success of digital, gate-based, classical computation, much of this effort has focused on gate based digital quantum computation. There is an alternative, however, which harnesses our understanding of physical process rather more directly. Nature is rather good at solving problems such as finding the most efficient way to arrange a collection of atoms into a crystal. Nature achieves this by gradually reducing the temperature of a system so that it can eventually settle to its lowest energy state - a process known as thermal annealing. This is used in a range of classical optimization algorithms. A quantum version of this, originally known as quantum annealing - now known as adiabatic quantum computation - may ultimately prove to be more effective for quantum computation than the gate based model. Indeed, a Canadian company, D-wave Systems, has attempted to make just such a computer with some promising initial results. Interpreting such attempts is difficult, however, since the failure mode of an adiabatic quantum computation is a classical thermal anneal. This project aims to develop a systematic way to test whether an adiabatic quantum computation has taken place using a pragmatic, physics based approach. In doing so, new insights into how to optimize the performance of such a system will result.

United States