Francesco Rao

Wordom: a program for efficient analysis of molecular dynamics simulations

Wordom is a versatile program for manipulation of molecular dynamics trajectories and efficient analysis of simulations. Original tools in Wordom include a procedure to evaluate significance of sampling for principal component analysis as well as modules for clustering multiple conformations and evaluation of order parameters for folding and aggregation. The program was developed with special emphasis on user-friendliness, effortless addition of new modules and efficient handling of large sets of trajectories.

Wordom: A user-friendly program for the analysis of molecular structures, trajectories, and free energy surfaces

Wordom is a versatile, user‐friendly, and efficient program for manipulation and analysis of molecular structures and dynamics. The following new analysis modules have been added since the publication of the original Wordom paper in 2007: assignment of secondary structure, calculation of solvent accessible surfaces, elastic network model, motion cross correlations, protein structure network, shortest intra‐molecular and inter‐molecular communication paths, kinetic grouping analysis, and calculation of mincut‐based free energy profiles. In addition, an interface with the Python scripting language has been built and the overall performance and user accessibility enhanced. The source code of Wordom (in the C programming language) as well as documentation for usage and further development are available as an open source package under the GNU General Purpose License from http://wordom.sf.net.

Replica exchange molecular dynamics simulations of amyloid peptide aggregation

The replica exchange molecular dynamics (REMD) approach is applied to four oligomeric peptide systems. At physiologically relevant temperature values REMD samples conformation space and aggregation transitions more efficiently than constant temperature molecular dynamics (CTMD). During the aggregation process the energetic and structural properties are essentially the same in REMD and CTMD. A condensation stage toward disordered aggregates precedes the beta-sheet formation. Two order parameters, borrowed from anisotropic fluid analysis, are used to monitor the aggregation process. The order parameters do not depend on the peptide sequence and length and therefore allow to compare the amyloidogenic propensity of different peptides

Complex network analysis of free-energy landscapes

The kinetics of biomolecular isomerization processes, such as protein folding, is governed by a free-energy surface of high dimensionality and complexity. As an alternative to projections into one or two dimensions, the free-energy surface can be mapped into a weighted network where nodes and links are configurations and direct transitions among them, respectively. In this work, the free-energy basins and barriers of the alanine dipeptide are determined quantitatively using an algorithm to partition the network into clusters (i.e., states) according to the equilibrium transitions sampled by molecular dynamics. The network-based approach allows for the analysis of the thermodynamics and kinetics of biomolecule isomerization without reliance on arbitrarily chosen order parameters. Moreover, it is shown on low-dimensional models, which can be treated analytically, as well as for the alanine dipeptide, that the broad-tailed weight distribution observed in their networks originates from free-energy basins with mainly enthalpic character.

BslA is a self-assembling bacterial hydrophobin that coats the Bacillus subtilis biofilm

Biofilms represent the predominant mode of microbial growth in the natural environment. Bacillus subtilis is a ubiquitous Gram-positive soil bacterium that functions as an effective plant growth-promoting agent. The biofilm matrix is composed of an exopolysaccharide and an amyloid fiber-forming protein, TasA, and assembles with the aid of a small secreted protein, BslA. Here we show that natively synthesized and secreted BslA forms surface layers around the biofilm. Biophysical analysis demonstrates that BslA can self-assemble at interfaces, forming an elastic film. Molecular function is revealed from analysis of the crystal structure of BslA, which consists of an Ig-type fold with the addition of an unusual, extremely hydrophobic “cap” region. A combination of in vivo biofilm formation and in vitro biophysical analysis demonstrates that the central hydrophobic residues of the cap are essential to allow a hydrophobic, nonwetting biofilm to form as they control the surface activity of the BslA protein. The hydrophobic cap exhibits physiochemical properties remarkably similar to the hydrophobic surface found in fungal hydrophobins; thus, BslA is a structurally defined bacterial hydrophobin. We suggest that biofilms formed by other species of bacteria may have evolved similar mechanisms to provide protection to the resident bacterial community.

Local modularity measure for network clusterizations.

Many complex networks have an underlying modular structure, i.e., structural subunits (communities or clusters) characterized by highly interconnected nodes. The modularity has been introduced as a measure to assess the quality of clusterizations. has a global view, while in many real-world networks clusters are linked mainly locally among each other (local cluster connectivity). Here we introduce a measure of localized modularity , which reflects local cluster structure. Optimization of and on the clusterization of two biological networks shows that the localized modularity identifies more cohesive clusters, yielding a complementary view of higher granularity.

Replica exchange molecular dynamics simulations of reversible folding

The replica exchange molecular dynamics (REMD) approach is applied to a 20-residue three-stranded antiparallel β-sheet peptide. At physiologically relevant temperature REMD samples conformational space much more efficiently than constant temperature molecular dynamics (MD) and allows reversible folding (312 folding events during a total simulation time of 32 μs). The energetic and structural properties during the folding process are similar in REMD and conventional MD at the temperature values where there is enough statistics for the latter. The simulation results indicate that the unfolded state contains a significant amount of non-native interactions especially at low temperature. The folding events consist of a gradual replacement of non-native contacts with native ones which is coupled with an almost monotonic decrease of the REMD temperature.

Three-Dimensional Infrared Spectroscopy of Isotope-Substituted Liquid Water Reveals Heterogeneous Dynamics

The dynamics of the hydrogen bond network of isotopically substituted liquid water are investigated with a new ultrafast nonlinear vibrational spectroscopy, three-dimensional infrared spectroscopy (3D-IR). The 3D-IR spectroscopy is sensitive to three-point frequency fluctuation correlation functions, and the measurements reveal heterogeneous structural relaxation dynamics. We interpret these results as subensembles of water which do not interconvert on a half picosecond time scale. We connect the experimental results to molecular dynamics (MD) simulations, performing a line shape analysis as well as complex network analysis.

Protein dynamics investigated by inherent structure analysis.

Molecular dynamics (MD) simulations provide essential information about the thermodynamics and dynamics of proteins. To construct the free-energy surface from equilibrium trajectories, it is necessary to group the individual snapshots in a meaningful way. The inherent structures (IS) are shown to provide an appropriate discretization of the trajectory and to avoid problems that can arise in clustering algorithms that have been employed previously. The IS-based approach is illustrated with a 30-ns room temperature “native” state MD simulation of a 10-residue peptide in a β-hairpin conformation. The transitions between the IS are used to construct a configuration space network from which a one-dimensional free-energy profile is obtained with the mincut method. The results demonstrate that the IS approach is useful and that even for this simple system, there exists a nontrivial organization of the native state into several valleys separated by barriers as high as 3 kcal/mol. Further, by introducing a coarse-grained network, it is demonstrated that there are multiple pathways connecting the valleys. This scenario is hidden when the snapshots of the trajectory are used directly with rmsd clustering to compute the free-energy profile. Application of the IS approach to the native state of the PDZ2 signaling domain indicates its utility for the study of biologically relevant systems.

Networks in cell biology

Introduction 1. Network views of the cell Paolo De Los Rios and Michele Vendruscolo 2. Transcriptional regulatory networks Sarath Chandra Janga and M. Madan Babu 3. Transcription factors and gene regulatory networks Matteo Brilli, Elissa Calistri and Pietro Lio 4. Experimental methods for protein interaction identification Peter Uetz, Bjorn Titz, Seesandra V. Rajagopala and Gerard Cagney 5. Modeling protein interaction networks Francesco Rao 6. Dynamics and evolution of metabolic networks Daniel Segre 7. Hierarchical modularity in biological networks: the case of metabolic networks Erzsebet Ravasz Regan 8. Signalling networks Gian Paolo Rossini Appendix 1. Complex networks: from local to global properties D. Garlaschelli and G. Caldarelli Appendix 2. Modelling the local structure of networks D. Garlaschelli and G. Caldarelli Appendix 3. Higher-order topological properties S. Ahnert, T. Fink and G. Caldarelli Appendix 4. Elementary mathematical concepts A. Gabrielli and G. Caldarelli References.