Progress in ab initio modeling of biomolecules: methods and applications

Computer simulation methods based on first principles calculations are increasingly being used to study the structure, dynamics and function of biomolecules. Specifically, the explicit inclusion of the evolving electronic structure (for example by means of Density Functional Theory) in simulations allows for a proper description of e.g. enzymatic reactions and drugs activity. This workshop aims to bring together several researchers active in this field with the double purpose of (i) exchanging the expertise and the progress done in the last few years, and (ii) to envisage strategies for the next future which can increase the effectiveness and scientific impact of this field of research.

While considerable effort in computational life science is focused on gene sequence and on a mesoscopic description of protein-protein interaction, a detailed microscopic understanding of the activity of biomolecules plays an important role and represents a major scientific and computational challenge. The ab initio simulations constitute a crucial tool, complementary to experiments, to elucidate at the atomic level the interplay between microscopic structure and function of a biological system. We know, for example, that a single mutation changing one amino acid in a protein can have dramatic effects on a given organism. To understand such effects, molecular biologists study the interaction of a protein with other molecules, which may be small ligands or other proteins. In the laboratory they can identify a region of tens or a hundred amino acids which are responsible for some specific action. Ab initio simulation can then pinpoint more precisely where and how the interaction actually works and what effect the mutation has. Such detailed understanding can be a useful ingredient in drug design, for example knowing whether the mutation makes the binding to the other molecule too weak or too strong. These studies can also have an impact on optoelectronic, enabling for instance the design of biomolecules with properly tuned optical properties by selective mutations.

In this workshop we will discuss methodological developments within ab initio simulations and recent efforts to broaden the range of applications to more complex systems. There are a number of technical problems in ab initio simulations which are not unique to biological applications but are particularly severe and unavoidable there. (i) A serious limitation is the number of atoms in a simulation, which can only cover the central active region of a protein though longer ranged electrostatic and elastic forces are also important. Therefore a large effort has been devoted recently in the development of hybrid methods which include the protein environment around the active site by using a classical force field approach. Linear scaling methods are also being developed to increase the size of the system treated with ab initio methods (ii) The correct calculation of hydrogen bonds and Van der Waals interactions, as well as the correct description of spin states in transition metal complexes present throughout biological systems, are particularly sensitive to the precise choice of correlation and exchange functional in the Density Functional Theory method. We will thus also discuss progress done in improved functionals and the comparison with other ab initio many body calculations. (iii) Another issue is the time scale of biological processes that are often very slow compared to the atomic motion so that one has to invoke and compute activated processes through complex pathways. Moreover, biological processes take place at room temperature and therefore it is crucial to calculate efficiently free energy barrier and the lowest free energy reaction path.

The following main topics will be discussed during the workshop:

Drug-DNA interaction Photo-activated biological processes Structure/functionality changes induced by mutation Hybrid methods Linear scaling methods Excited state dynamics Improved exchange-correlation functionals Metadynamics and Free energy calculation Simulation and interpretation of spectroscopic probes (e.g. NMR chemical shift)