| Autor: |
Kalmer TL; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240-0002, United States., Ancajas CMF; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240-0002, United States., Cohen CI; Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37240-0002, United States.; Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37240-7917, United States., McDaniel JM; Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37240-0002, United States., Oyedele AS; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240-0002, United States., Thirman HL; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee 37240-7935, United States.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.; Chemical & Physical Biology Program, Vanderbilt University, Nashville, Tennessee 37232-0301, United States., Walker AS; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37240-0002, United States.; Department of Biological Sciences, Vanderbilt University, Nashville, Tennessee 37240-0002, United States.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States.; Evolutionary Studies Initiative, Vanderbilt University, Nashville, Tennessee 37240-0002, United States. |
| Abstrakt: |
Dihydrofolate reductase (DHFR), due to its universality and the depth with which it has been studied, is a model system in the study of protein dynamics. Myriad previous works have identified networks of residues in positions near to and remote from the active site that are involved in the dynamics. For example, specific mutations on the Met20 loop in Escherichia coli DHFR (N23PP/S148A) are known to disrupt millisecond-time scale motions as well as reduce catalytic activity. However, how and if networks of dynamically coupled residues influence the evolution of DHFR is still an unanswered question. In this study, we first identify, by statistical coupling analysis and molecular dynamic simulations, a network of coevolving residues that possesses increased correlated motions. We then go on to show that allosteric communication in this network is knocked down in N23PP/S148A mutant E. coli DHFR. We also identify two sites in the human DHFR sector which may accommodate the Met20 loop double proline motif. Finally, we demonstrate a concerted evolutionary change in the human DHFR allosteric networks, which maintains dynamic communication. These findings strongly implicate protein dynamics as a driving force for evolution. |
