Section: Overall Objectives

Computational Challenges in Structural Biology

Many of the processes within living organisms can be studied and understood in terms of biochemical interactions between large macromolecules such as DNA, RNA, and proteins. To a first approximation, DNA may be considered to encode the blueprint for life, whereas proteins and RNA make up the three-dimensional (3D) molecular machinery. Many biological processes are governed by complex systems of proteins which interact cooperatively to regulate the chemical composition within a cell or to carry out a wide range of biochemical processes such as photosynthesis, metabolism, and cell signalling, for example. It is becoming increasingly feasible to isolate and characterise some of the individual protein components of such systems, but it still remains extremely difficult to achieve detailed models of how these complex systems actually work. Consequently, a new multidisciplinary approach called integrative structural biology has emerged which aims to bring together experimental data from a wide range of sources and resolution scales in order to meet this challenge [69], [56].

Understanding how biological systems work at the level of 3D molecular structures presents fascinating challenges for biologists and computer scientists alike. Despite being made from a small set of simple chemical building blocks, protein molecules have a remarkable ability to self-assemble into complex molecular machines which carry out very specific biological processes. As such, these molecular machines may be considered as complex systems because their properties are much greater than the sum of the properties of their component parts.

The overall objective of the Capsid team is to develop algorithms and software to help study biological systems and phenomena from a structural point of view. In particular, the team aims to develop algorithms which can help to model the structures of large multi-component biomolecular machines and to develop tools and techniques to represent and mine knowledge of the 3D shapes of proteins and protein-protein interactions. Thus, a unifying theme of the team is to tackle the recurring problem of representing and reasoning about large 3D macromolecular shapes. More specifically, our aim is to develop computational techniques to represent, analyse, and compare the shapes and interactions of protein molecules in order to help better understand how their 3D structures relate to their biological function. In summary, the Capsid team is organized according to two research axes whose complementarity constitutes an original contribution to the field of structural bioinformatics:

  • Axis 1: New Approaches for Knowledge Discovery in Structural Databases,

  • Axis 2: Integrative Multi-Component Assembly and Modeling.

As indicated above, structural biology is largely concerned with determining the 3D atomic structures of proteins, RNA, and DNA molecules, and then using these structures to study their biological properties and interactions. Each of these activities can be extremely time-consuming. Solving the 3D structure of even a single protein using X-ray crystallography or nuclear magnetic resonance (NMR) spectroscopy can often take many months or even years of effort. Even simulating the interaction between two proteins using a detailed atomistic molecular dynamics simulation can consume many thousands of CPU-hours. While most X-ray crystallographers, NMR spectroscopists, and molecular modelers often use conventional sequence and structure alignment tools to help propose initial structural models through the homology principle, they often study only individual structures or interactions at a time. Due to the difficulties outlined above, only relatively few research groups are able to solve the structures of large multi-component systems.

Similarly, most current algorithms for comparing protein structures, and especially those for modeling protein interactions, work only at the pair-wise level. Of course, such calculations may be accelerated considerably by using dynamic programming (DP) or fast Fourier transform (FFT) techniques. However, it remains extremely challenging to scale up these techniques to model multi-component systems. For example, the use of high performance computing (HPC) facilities may be used to accelerate arithmetically intensive shape-matching calculations, but this generally does not help solve the fundamentally combinatorial nature of many multi-component problems. It is therefore necessary to devise heuristic hybrid approaches which can be tailored to exploit various sources of domain knowledge. We therefore set ourselves the following main computational objectives:

  • classify and mine protein structures and protein-protein interactions,

  • develop multi-component assembly techniques for integrative structural biology.