134 CATALYZING INQUIRY
5.4.2.1 Cellular Modeling and Simulation Efforts,
The preceding discussion has been highly abstract. This section provides some illustrations of how
modeling and simulation have value across a variety of subfields in biology. No claim is made to
comprehensiveness, but the committee wishes to illustrate the utility of modeling and simulations at
levels of organization from gene to ecosystem.
5.4.1 Molecular and Structural Biology,
5.4.1.1 Predicting Complex Protein Structures,
Interactions between proteins are crucial to the functioning of all cells. While there is much experi-
mental information being gathered regarding protein structures, many interactions are not fully under-
stood and have to be modeled computationally. The topic of computational prediction of protein-
protein structure remains to be solved and is one of the most active areas of research in bioinformatics
and structural biology.
ZDOCK and RDOCK are two computer programs that address this problem, also known as protein
docking.^37 ZDOCK is an initial stage protein docking program that performs a full search of the relative
orientations of two molecules (referred to by convention as the ligand and receptor) to determine their
best fit based on surface complementarity, electrostatics and desolvation. The efficiency of the algo-
rithm is enhanced by discretizing the molecules onto a grid and performing a fast Fourier transform
(FFT) to quickly explore the translational degrees of freedom.
RDOCK takes as input the ZDOCK predictions and improves them using two steps. The first step is
to improve the energetics of the prediction and remove clashes by performing small movements of the
predicted complex, using a program known as CHARMM. The second step is to rescore these mini-
mized predictions with more detailed scoring functions for electrostatics and desolvation.
The combination of these two algorithms has been tested and verified with a benchmark set of
proteins collected for use in testing docking algorithms. Now at version 2.0, this benchmark is publicly
available and contains 87 test cases. These test cases cover a breadth of interactions, such as antibody-
antigen, and cases involving significant conformational changes.
The ZDOCK-RDOCK programs have consistently performed well in the international docking
competition CAPRI (Figure 5.1). Some notable predictions were for the Rotavirus VP6/Fab (50 of 52
contacting residues correctly predicted), and SAG-1/Fab complex (61 of 70 contacts correct), and the
cellulosome cohesion-dockerin structure (50 of 55 contacts correct). In the first two cases, the number of
contacts in the ZDOCK-RDOCK predictions were the highest among all participating groups.
5.4.1.2 A Method to Discern a Functional Class of Proteins,
The DNA-binding helix-turn-helix structural motif plays an essential role in a variety of cellular
pathways that include transcription, DNA recombination and repair, and DNA replication. Current
methods for identifying the motif rely on amino acid sequence, but since members of the motif belong
to different sequence families that have no sequence homology to each other, these methods have been
unable to identify all motif members.
A new method based on three-dimensional structure was created that involved the following
steps:^38 (1) choosing a conserved component of the motif, (2) measuring structural features relative
(^37) For more information, see http://zlab.bu.edu.
(^38) W.A. McLaughlin and H.M. Berman, “Statistical Models for Discerning Protein Structures Containing the DNA-binding
Helix-Turn-Helix Motif,” Journal of Molecular Biology 330(1):43-55, 2003.