Abstract
The role of mechanical force in cellular processes is increasingly revealed by single molecule experiments and simulations of force-induced transitions in proteins. How the applied force propagates within proteins determines their mechanical behavior yet remains largely unknown. We present a new method based on molecular dynamics simulations to disclose the distribution of strain in protein structures, here for the newly determined high-resolution crystal structure of I27, a titin immunoglobulin (IG) domain. We obtain a sparse, spatially connected, and highly anisotropic mechanical network. This allows us to detect load-bearing motifs composed of interstrand hydrogen bonds and hydrophobic core interactions, including parts distal to the site to which force was applied. The role of the force distribution pattern for mechanical stability is tested by in silico unfolding of I27 mutants. We then compare the observed force pattern to the sparse network of coevolved residues found in this family. We find a remarkable overlap, suggesting the force distribution to reflect constraints for the evolutionary design of mechanical resistance in the IG family. The force distribution analysis provides a molecular interpretation of coevolution and opens the road to the study of the mechanism of signal propagation in proteins in general.
Highlights
Cellular functions such as growth, motility, and signaling are tightly coupled with mechanical forces [1,2,3]
How mechanical stress propagates through proteins to induce a certain mechanical response is currently unknown
The method is based on molecular dynamics simulations during which we calculate changes in interatomic forces, here caused by pulling the protein
Summary
Cellular functions such as growth, motility, and signaling are tightly coupled with mechanical forces [1,2,3]. A fundamental question is how a protein of mechanical function has been evolutionarily designed to withstand and transmit high levels of stress. Analysis and design of macroscopic structures such as cells, organs, or implants is routinely guided by the calculation of force propagation to predict and improve mechanical response [5,6]. For different titin immunoglobulin (IG) domains and engineered variants thereof, unfolding forces have been measured and rupture mechanisms inferred [12,13,14,15,16]. These data provide important insight into the load-bearing structural motifs of IG. It is an obvious assumption that force propagates through the structure to parts which, being distant from the application site of the perturbation, cannot be straightforwardly inferred from unfolding forces
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