| Autor: |
Kalmer TL; Department of Chemistry, Vanderbilt University Nashville, TN, USA., Ancajas CMF; Department of Chemistry, Vanderbilt University Nashville, TN, USA., Cohen CI; Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.; Center for Structural Biology, Vanderbilt University, Nashville, TN, USA., McDaniel JM; Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA., Oyedele AS; Department of Chemistry, Vanderbilt University Nashville, TN, USA., Thirman HL; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.; Chemical & Physical Biology Program, Vanderbilt University, Nashville, TN, USA., Walker AS; Department of Chemistry, Vanderbilt University Nashville, TN, USA.; Department of Biological Sciences, Vanderbilt University, Nashville, TN, USA.; Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.; Evolutionary Studies Initiative, Vanderbilt University, Nashville, TN, USA. |
| Abstrakt: |
The role of dynamics in enzymatic function is a highly debated topic. Dihydrofolate reductase (DHFR), due to its universality and the depth with which it has been studied, is a model system in this debate. Myriad previous works have identified networks of residues in positions near to and remote from the active site that are involved in dynamics and others that are important for catalysis. For example, specific mutations on the Met20 loop in E. coli DHFR (N23PP/S148A) are known to disrupt millisecond-timescale motions and 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, which possess increased correlated motions. We then go on to show that allosteric communication in this network is selectively knocked down in N23PP/S148A mutant E. coli DHFR. Finally, we identify two sites in the human DHFR sector which may accommodate the Met20 loop double proline mutation while preserving dynamics. These findings strongly implicate protein dynamics as a driving force for evolution. |
