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

据说DNA和RNA提供了制造细胞和生物体的蓝图，而蛋白质则负责使它们工作。问题是：蛋白质能执行我们定义的任何功能吗？答案是：可能，但还不是现在。关键是天然蛋白质似乎在某些方面受到限制。蛋白质的3D形状（结构）当然也是如此。一个例子是哺乳动物抗体，一些病毒外壳蛋白和植物中捕获光能的某些蛋白质具有共同的3D结构（称为β-三明治折叠），但它们具有不同的化学和功能。因此，自然界似乎再次使用少量的蛋白质结构，通过改变附加在它们上面的化学物质来改变功能。蛋白质科学目前的问题包括：除了这些天然蛋白质结构之外还有什么？非天然蛋白质的结构和功能是可能的吗？后者的答案几乎肯定是肯定的，但问题是如何访问，制作和确认它们？这就是蛋白质设计的任务，它解决了这些问题，也可能为新的蛋白质催化剂、诊断和药物提供途径。蛋白质结构复杂，有数千个原子在空间中精确排列。它们是氨基酸结构单元的线性链，通常有数百个单元长。在蛋白质中，有20种氨基酸类型，它们具有不同的大小，形状和化学性质。氨基酸链上沿着排列的顺序--称为序列--决定了蛋白质的结构和功能：改变氨基酸的类型和顺序，整体的形状和功能就会改变。此外，这20种不同的氨基酸可以排列成实际上无限多的任何长度的蛋白质链，这意味着有无限多的形状。在此基础上，设计蛋白质听起来很难，但有希望：而不是预测每一条可能的蛋白质链是如何折叠的，蛋白质设计者“简单地”必须找到最适合--因此最好地定义--其目标蛋白质结构的氨基酸序列。我们设计蛋白质的方法与该领域的许多其他方法不同。迄今为止，其他人所做的许多出色工作都是从天然蛋白质中学习和模仿的。然而，我们建议从头开始构建蛋白质，使用定义蛋白质设计师希望它采用的可能形状的方程。这被称为蛋白质参数化设计。它提供了一条通往全新蛋白质结构并最终实现新功能的途径。我们将开发计算机程序来完成这项工作，我们的软件ISAMBARD将使用传统的方法，即使用键盘，将设计蛋白质的指令输入计算机。我们将使ISAMBARD免费提供给所有学术和非营利用户。我们将通过制造前所未见的蛋白质来对ISAMBARD进行实验测试。我们还将与虚拟现实软件设计方面的工业合作伙伴专家合作，开发ISAMBARD-VR，让用户真正“进入”在计算机中构建蛋白质的过程。这将使任何人都可以使用蛋白质设计，无论他/她是否熟悉计算机。通过ISAMBARD-VR，用户将能够交互和直观地定义他们正在设计的形状蛋白质。这将被传递到ISAMBARD，ISAMBARD将优化设计并找到最适合和定义它的序列。这将使用从天然蛋白质如何组合在一起学到的规则，用户直觉和计算机算法的组合，以有效地搜索由这些不同设计约束定义的氨基酸的许多可能组合。最后，使用ISAMBARD-VR，我们将使用机器学习方法从工作中的设计师那里“观察和学习”。通过这种方式，我们的目标不仅是改进ISAMBARD，ISAMBARD-VR，而且是一般的蛋白质设计。

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.