Natural selection of more designable folds: A mechanism for thermophilic adaptation

Abstract

An open question of great interest in biophysics is whether variations in structure cause protein folds to differ in the number of amino acid sequences that can fold to them stably, i.e., in their designability. Recently, we have shown that a novel quantitative measure of a fold's tertiary topology, called its contact trace, strongly correlates with the fold's designability. Here, we investigate the relationship between a fold's contact trace and its relative frequency of usage in mesophilic vs. thermophilic eubacteria. We observe that thermophilic organisms exhibit a bias toward using folds of higher contact trace when compared with mesophiles. We establish this difference both for the distributions of folds at the whole-proteome level and also through more focused structural comparisons of orthologous proteins. Our findings suggest that thermophilic adaptation in bacterial genomes occurs in part through natural selection of more designable folds, pointing to designability as a key component of protein fitness.U nderstanding the adaptations that enable thermophilic organisms to survive at extreme temperatures is a challenge that has interested researchers since 1897 (1), and great strides have been made along this line of inquiry since the recent publications of complete genomes for several hyperthermophilic species (2). However, most research in this area has focused on amino acid sequence variations that increase the thermodynamic stability of thermophilic proteins while leaving their structures unchanged (2, 3). Far less is known about what structural differences exist between thermophilic and mesophilic proteomes. One interesting possibility is that a thermophilic bias in structure may manifest as a preference for folds that are able to accommodate a large number of low-energy sequences, because such folds have a higher probability of being able to maintain their stability while adapting by mutation to new pressures. This hypothesis relates to another problem of great interest in biophysics: how the structural topology of a protein fold affects its designability (4-9). Here, we present results that point to an important connection between these two problems. Making use of what is known analytically about the relationship between a fold's topology and its designability and thermostability, we report an adaptation mechanism of thermophillic bacteria: one that proceeds by selection of more designable folds.Recently, a new theoretical treatment of designability has been developed within the framework of a residue-residue contact Hamiltonian (10). This Hamiltonian is a well established model for protein energetics that defines the conformational energy of a polypeptide chain as the sum of the pairwise interaction energies of all of the amino acid pairs whose ␣ carbons are separated by a distance less than some contact cutoff, typically chosen to be Ϸ7.5 Å (11). More formally, for a chain of length N with a monomer alphabet containing M amino acid types (of course, M ϭ 20 for real proteins), we can define the ene...

Physics and evolution of thermophilic adaptation

“…Thus, both amino acid content and packing density show a difference between hyperthermophilic archaea (Pyrococcus) and bacteria (A. aeolicus and T. maritima). Increased packing density in archaea correlates with an increased contact density observed in several thermophilic proteomes (22) and higher contact density for the last universal common ancestor (LUCA) domains͞folds (23). Together with results of unfolding simulations (Fig.…”

“…A limited number of available folds (22,37, and 42 for A. aeolicus, P. furiosus͞horikoshii͞abyssi, and T. maritima, respectively) is a caveat of the analysis. However, even these sets reveal a significant difference between mean values of distributions of number of contact per residue.…”

Shape-dependent designability studies of lattice proteins

“…A correlation has been found between this structural determinant of designability and the size of a protein family, accounting for the evolutionary age of the family (44). It has also been discovered that proteins in thermophilic organisms, which presumably have been selected for higher thermodynamic stability, are on average more designable than those of non-thermophilic organisms (45). Our lattice protein study suggests the possibility of a correlation between protein designability and the radius of gyration (when average number of contacts per residue is used) as well as surface features in real proteins.…”

Predicting Virus Evolution: The Relationship between Genetic Robustness and Evolvability of Thermotolerance

“…This notion is supported by the observation that microbial species thriving in extremely high-temperature environments typically possess proteins with unusually stable folding patterns that facilitate growth and survival under thermodynamic stress at elevated temperatures (Huber and Stetter 2001;Sterner and Liebl 2001;England et al 2003). The widespread existence of heat shock protein chaperones in biological systems offers further evidence that protein stability under heat shock is a target of natural selection (e.g., in yeast species) (Craig et al 1993;Parsell et al 1993) .…”