Effective connectivity profile: a structural representation that evidences the relationship between protein structures and sequences.
The complexity of protein structures calls for simplified representations of their topology. The simplest possible mathematical description of a protein structure is a one-dimensional profile representing, for instance, buriedness or secondary structure. This kind of representation has been introduced for studying the sequence to structure relationship, with applications to fold recognition. Here we define the effective connectivity profile (EC), a network theoretical profile that self-consistently represents the network structure of the protein contact matrix. The EC profile makes mathematically explicit the relationship between protein structure and protein sequence, because it allows predicting the average hydrophobicity profile (HP) and the distributions of amino acids at each site for families of homologous proteins sharing the same structure. In this sense, the EC provides an analytic solution to the statistical inverse folding problem, which consists in finding the statistical properties of the set of sequences compatible with a given structure. We tested these predictions with simulations of the structurally constrained neutral (SCN) model of protein evolution with structure conservation, for single- and multi-domain proteins, and for a wide range of mutation processes, the latter producing sequences with very different hydrophobicity profiles, finding that the EC-based predictions are accurate even when only one sequence of the family is known. The EC profile is very significantly correlated with the HP for sequence-structure pairs in the PDB as well. The EC profile generalizes the properties of previously introduced structural profiles to modular proteins such as multidomain chains, and its correlation with the sequence profile is substantially improved with respect to the previously defined profiles, particularly for long proteins. Furthermore, the EC profile has a dynamic interpretation, since the EC components are strongly inversely related with the temperature factors measured in X-ray experiments, meaning that positions with large EC component are more strongly constrained in their equilibrium dynamics. Last, the EC profile allows to define a natural measure of modularity that correlates with the number of domains composing the protein, suggesting its application for domain decomposition. Finally, we show that structurally similar proteins have similar EC profiles, so that the similarity between aligned EC profiles can be used as a structure similarity measure, a property that we have recently applied for protein structure alignment. The code for computing the EC profile is available upon request writing to ubastolla@cbm.uam.es, and the structural profiles discussed in this article can be downloaded from the SLOTH webserver http://www.fkp.tu-darmstadt.de/SLOTH/.
Centro de Biología Molecular Severo Ochoa, (CSIC-UAM), Cantoblanco, 28049 Madrid, Spain. ubastolla@cbm.uam.es
Ugo
U
Bastolla
Angel R
AR
Ortíz
Markus
M
Porto
Florian
F
Teichert
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D003198:Computer Simulation; D017124:Conserved Sequence; D030562:Databases, Protein; D019143:Evolution, Molecular; D057927:Hydrophobic and Hydrophilic Interactions; D011506:Proteins / Q000737:chemistry*; D013696:Temperature
D000596:Amino Acids; D011506:Proteins