Rational computational protein design in ISAMBARD: new approaches, folds and functions

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It is said that DNA and RNA provide the blueprint to make cells and organisms, while proteins do everything else to make them work. The question is: can proteins perform any function that we define? The answer is: probably, but not just yet.The point is that natural proteins appear to be limited in some ways. This is certainly the case for the 3D shapes (structures) of proteins. An example is that mammalian antibodies, some viral coat proteins, and certain proteins that trap light energy in plants share a common 3D structure (called a beta-sandwich fold), but they have different chemistries and functions. Thus, nature appears to use a small number of protein structures over again, altering functions by changing the chemistry appended onto them.Current questions in protein science include: what lies beyond these natural protein structures? Are non-natural protein structures and functions possible? The answer to the latter is almost certainly yes, but the problem is how to access, make and confirm them? This is the task of protein design, which addresses these questions and also potentially provides routes to new protein catalysts, diagnostics and pharmaceuticals.Protein structures are complicated, with thousands of atoms arranged precisely in space. They are linear chains of amino-acid building blocks, often many hundreds of units long. In proteins, there are 20 amino-acid types, which have different sizes, shapes and chemistries. The order of the amino-acid blocks along the chain-called the sequence-determines the protein's structure and function: change the types and order of the amino acids, and the overall shape and function change. Moreover, the 20 different amino acids can be arranged in an effectively infinite number of protein chains of any length, which means that there is an infinite number of shapes.On this basis, designing proteins sounds difficult, but there is hope: rather than predicting how each of the possible protein chains folds up, protein designers "simply" have to find a sequence of amino acids that best fits-and therefore best defines-their targeted protein structure. Computers provide the means to do this.Our approach to designing proteins is different from many others in the field. Much of the excellent work done by others to date learns from and mimics natural proteins. However, we propose to build proteins from scratch using equations that define the possible shapes that the protein designer wants it to adopt. This is called parametric protein design. It offers a route to entirely new protein structures and eventually to new functions. We will develop computer programs to do this.Our software, ISAMBARD, will use traditional ways of inputting instructions for designing proteins into the computer, i.e. using the keyboard. We will make ISAMBARD freely available to all academic and not-for-profit users. We will test ISAMBARD experimentally by making proteins that have never been seen before.Working with an industrial partner expert in virtual reality software design, we will also develop ISAMBARD-VR, which will allow users literally to "step into" the process of building a protein in the computer. This will make protein design accessible to anyone regardless of his/her familiarity with computers. Through ISAMBARD-VR, users will be able to define the shape protein they are designing interactively and intuitively. This will then be passed to ISAMBARD, which will optimise the design and find sequences that best fit and define it. This will use a combination of rules learned from how natural proteins fit together, user intuition, and computer algorithms to search efficiently through the many possible combinations of amino acids defined by these various design constraints.Finally, using ISAMBARD-VR, we will "watch and learn" from the designers at work using machine-learning methods. In this way, we aim not only to improve ISAMBARD, ISAMBARD-VR, but protein design in general.