In recognition that December is AIDS Awareness Month, we asked Klaus Schulten, Professor of Physics at the University of Illinois at Urbana-Champaign and a true leader in the field of computational biophysics, and Juan Perilla, member of the Theoretical and Computational Biophysics Group at the University of Illinois at Urbana-Champaign, to share some information about their research related to AIDS.

• What is the connection between your research and AIDS?

AIDS is caused by the human immunodeficiency virus (HIV). The virus has the ability to infect non-dividing cells, which means that it first needs to establish a pathway into the cell and then permeate the cell's nucleus. For this purpose it enters a cell and recruits cell factors to assist the orchestration of a complex process leading to insertion of the viral RNA into the cell’s genome. The infection process involves the capsid surface, a protein shell that encases the viral genome; we just don't know how this process happens. The capsid is a natural therapeutical target as ape cells prevent infection by targeting the capsid. In an experimental-computational collaboration we have successfully established the atomic-level structure of the HIV capsid and could characterize the capsid surface properties, capsid surface processes as well as capsid surface interactions with host proteins and small molecules.

• Why is your research important to those concerned about these diseases?

HIV is a majestic example of a viral capsid. We are studying the last defense mechanism the virus faces before insertion of viral genes into the cell's genome. We ask: How can the capsid break into the cell's genomes without starting any alarms, even with obtaining help from the cell.

• How did you get into this area of research?

We are known for solving structures of  macromolecular assemblies involving up to millions of atoms, namely the molecular dynamics flexible fitting method.  The computational method combines crystallographic, NMR  and electron microscopy data and, thereby, yields structures that can be probed directly in all-atom simulations..  The medical researchers approached us because of the enormous size of the HIV capsid, namely about 4 million atoms.

• How long have you been working on it?

Fortunately, when the medical researchers approached us we had just scaled up our modeling software from a million to 100million atoms which had taken us about 5 years of intense work; we also had got our programs to run successfully on the new generation of petascale computers that were needed for the study of multi-million atom structures.  Solving the HIV capsid structure required then over a year of intense work by several people as we needed experts on every corner of the field.  Also extremely fortunately, when the experimentalists called,  the new computers were made available to us as a testbed such that we got very early and very generous computer time allocations without much red tape.

• Do you receive federal funding for this work? If so, from what agency?

The computers used for our work are funded by NSF and DOE.  The software development is funded for over two decades now by NIH.  Our medical collaborators are funded by NIH; a key part of our computational science is funded by NSF.  The funding and support by those agencies has been outstanding.

• Have you had any surprise findings thus far?

We have had the unique opportunity to test our wildest ideas. For instance, what if you apply an electric field across the capsid, can you "program" capsid disassembly? Is it possible to study the capsid as a whole and analyze its collective behavior? The answer to the second question is "yes".  In fact, we found that the capsid itself acts as a film with considerable plasticity.  We learnt that rupturing the capsid through drugs is less straightforward than obstructing its cooperation with cellular factors during the intra-cell infection process.

• What is particularly interesting about the work from the perspective of other researchers?

First, the structure of the HIV capsid establishes, so-to-speak, a new base camp on reaching the top of the mountain, namely flexible treatments against HIV.  The structure is not an end in itself, but only a better starting point than was available previously as the structure captures an entire HIV capsid and includes the complete chemical detail one needs to know to develop new drugs.

Second, the work demonstrated the feasibility of solving the huge structures found in living cells and subjecting them to molecular dynamics simulations.  The software tools seemed unfeasible for a long time and researchers thought they needed to envoke drastically simplified descriptions in the form of course-grained simulations, but now all-atom simulations for multi-million atom systems have become overnight routine, permitting cellular biologists to model, for example,  large scale aggregation of proteins that arises all over living cells and to investigate the biological function of such aggregates in detail.   Modeling has taken a key step from molecule-scale towards cell-scale studies without sacrificing the accuracy of the description and this opens up a new field of study.

• What is particularly interesting about the work from the perspective of the public?

The treatment of AIDS has made much progress recently, but the virus exhibits great adaptability such that new treatments need to be found constantly.  Having resolved the target, namely the HIV capsid, in chemical detail will suggest new drugs.

• Do you have a cool image you want to share with the blog post related to this research?

Yes, see (50 MB!):  http://www.ks.uiuc.edu/Publications/Stories/2014calendar/