Transport Dynamics of MtrD: An RND Multidrug Efflux Pump from Neisseria gonorrhoeae
The MtrCDE system confers multidrug resistance to Neisseria gonorrhoeae, the causative agent of gonorrhea. Using free and directed molecular dynamics (MD) simulations, we analyzed the interactions between MtrD and azithromycin, a transport substrate of MtrD, and a last-resort clinical treatment for...
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| Veröffentlicht in: | Biochemistry (Easton) 2021-10, Vol.60 (41), p.3098-3113 |
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| creator | McCormick, Lauren A. Mertz, Sarah B. Park, Chanyang Wise, John G. |
| description | The MtrCDE system confers multidrug resistance to Neisseria gonorrhoeae, the causative agent of gonorrhea. Using free and directed molecular dynamics (MD) simulations, we analyzed the interactions between MtrD and azithromycin, a transport substrate of MtrD, and a last-resort clinical treatment for multidrug-resistant gonorrhea. We then simulated the interactions between MtrD and streptomycin, an apparent nonsubstrate of MtrD. Using known conformations of MtrD homologues, we simulated a potential dynamic transport cycle of MtrD using targeted MD techniques (TMD), and we noted that forces were not applied to ligands of interest. In these TMD simulations, we observed the transport of azithromycin and the rejection of streptomycin. In an unbiased, long-time scale simulation of AZY-bound MtrD, we observed the spontaneous diffusion of azithromycin through the periplasmic cleft. Our simulations show how the peristaltic motions of the periplasmic cleft facilitate the transport of substrates by MtrD. Our data also suggest that multiple transport pathways for macrolides may exist within the periplasmic cleft of MtrD. |
| doi_str_mv | 10.1021/acs.biochem.1c00399 |
| format | Article |
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Using free and directed molecular dynamics (MD) simulations, we analyzed the interactions between MtrD and azithromycin, a transport substrate of MtrD, and a last-resort clinical treatment for multidrug-resistant gonorrhea. We then simulated the interactions between MtrD and streptomycin, an apparent nonsubstrate of MtrD. Using known conformations of MtrD homologues, we simulated a potential dynamic transport cycle of MtrD using targeted MD techniques (TMD), and we noted that forces were not applied to ligands of interest. In these TMD simulations, we observed the transport of azithromycin and the rejection of streptomycin. In an unbiased, long-time scale simulation of AZY-bound MtrD, we observed the spontaneous diffusion of azithromycin through the periplasmic cleft. Our simulations show how the peristaltic motions of the periplasmic cleft facilitate the transport of substrates by MtrD. Our data also suggest that multiple transport pathways for macrolides may exist within the periplasmic cleft of MtrD.</description><identifier>ISSN: 0006-2960</identifier><identifier>ISSN: 1520-4995</identifier><identifier>EISSN: 1520-4995</identifier><identifier>DOI: 10.1021/acs.biochem.1c00399</identifier><identifier>PMID: 34609833</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Azithromycin - chemistry ; Azithromycin - metabolism ; Bacterial Proteins - chemistry ; Bacterial Proteins - metabolism ; Binding Sites ; Biological Transport ; Hydrogen Bonding ; Ligands ; Membrane Proteins - chemistry ; Membrane Proteins - metabolism ; Membrane Transport Proteins - chemistry ; Membrane Transport Proteins - metabolism ; Molecular Dynamics Simulation ; Neisseria gonorrhoeae - chemistry ; Protein Binding ; Streptomycin - chemistry ; Streptomycin - metabolism</subject><ispartof>Biochemistry (Easton), 2021-10, Vol.60 (41), p.3098-3113</ispartof><rights>2021 The Authors. 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Using free and directed molecular dynamics (MD) simulations, we analyzed the interactions between MtrD and azithromycin, a transport substrate of MtrD, and a last-resort clinical treatment for multidrug-resistant gonorrhea. We then simulated the interactions between MtrD and streptomycin, an apparent nonsubstrate of MtrD. Using known conformations of MtrD homologues, we simulated a potential dynamic transport cycle of MtrD using targeted MD techniques (TMD), and we noted that forces were not applied to ligands of interest. In these TMD simulations, we observed the transport of azithromycin and the rejection of streptomycin. In an unbiased, long-time scale simulation of AZY-bound MtrD, we observed the spontaneous diffusion of azithromycin through the periplasmic cleft. Our simulations show how the peristaltic motions of the periplasmic cleft facilitate the transport of substrates by MtrD. Our data also suggest that multiple transport pathways for macrolides may exist within the periplasmic cleft of MtrD.</description><subject>Azithromycin - chemistry</subject><subject>Azithromycin - metabolism</subject><subject>Bacterial Proteins - chemistry</subject><subject>Bacterial Proteins - metabolism</subject><subject>Binding Sites</subject><subject>Biological Transport</subject><subject>Hydrogen Bonding</subject><subject>Ligands</subject><subject>Membrane Proteins - chemistry</subject><subject>Membrane Proteins - metabolism</subject><subject>Membrane Transport Proteins - chemistry</subject><subject>Membrane Transport Proteins - metabolism</subject><subject>Molecular Dynamics Simulation</subject><subject>Neisseria gonorrhoeae - chemistry</subject><subject>Protein Binding</subject><subject>Streptomycin - chemistry</subject><subject>Streptomycin - metabolism</subject><issn>0006-2960</issn><issn>1520-4995</issn><issn>1520-4995</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EoqXwBUjISzZp_cjL7Kq2PKS2ICjryHbsNlUSBzuW6N-TqoElq9GMzp3RHABuMRpjRPCESzcWhZE7VY2xRIgydgaGOCIoCBmLzsEQIRQHhMVoAK6c23dtiJLwEgxoGCOWUjoEHxvLa9cY28L5oeZVIR00Gq5aO3-A0xq-r-dw5cu2yK3fwoXWpf-Gb75qoLamgmtVOKdsweHW1MbanVFcXYMLzUunbvo6Ap-Pi83sOVi-Pr3MpsuAExqxgKA4zLUKU5YgkgiSi5zwMBWUJ2mICdOCYRmLKNKRlIzJVHRzGumUKCZFzukI3J_2NtZ8eeXarCqcVGXJa2W8y0iUsJgiEqcdSk-otMY5q3TW2KLi9pBhlB1tZp3NrLeZ9Ta71F1_wItK5X-ZX30dMDkBx_TeeFt3__678gdwpILM</recordid><startdate>20211019</startdate><enddate>20211019</enddate><creator>McCormick, Lauren A.</creator><creator>Mertz, Sarah B.</creator><creator>Park, Chanyang</creator><creator>Wise, John G.</creator><general>American Chemical Society</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-5398-8794</orcidid></search><sort><creationdate>20211019</creationdate><title>Transport Dynamics of MtrD: An RND Multidrug Efflux Pump from Neisseria gonorrhoeae</title><author>McCormick, Lauren A. ; Mertz, Sarah B. ; Park, Chanyang ; Wise, John G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a2359-2064dfe4897027b2dbd2a48b3a784129fb91c6b55f5cc99c8b78435f82e9cbda3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Azithromycin - chemistry</topic><topic>Azithromycin - metabolism</topic><topic>Bacterial Proteins - chemistry</topic><topic>Bacterial Proteins - metabolism</topic><topic>Binding Sites</topic><topic>Biological Transport</topic><topic>Hydrogen Bonding</topic><topic>Ligands</topic><topic>Membrane Proteins - chemistry</topic><topic>Membrane Proteins - metabolism</topic><topic>Membrane Transport Proteins - chemistry</topic><topic>Membrane Transport Proteins - metabolism</topic><topic>Molecular Dynamics Simulation</topic><topic>Neisseria gonorrhoeae - chemistry</topic><topic>Protein Binding</topic><topic>Streptomycin - chemistry</topic><topic>Streptomycin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McCormick, Lauren A.</creatorcontrib><creatorcontrib>Mertz, Sarah B.</creatorcontrib><creatorcontrib>Park, Chanyang</creatorcontrib><creatorcontrib>Wise, John G.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Biochemistry (Easton)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>McCormick, Lauren A.</au><au>Mertz, Sarah B.</au><au>Park, Chanyang</au><au>Wise, John G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Transport Dynamics of MtrD: An RND Multidrug Efflux Pump from Neisseria gonorrhoeae</atitle><jtitle>Biochemistry (Easton)</jtitle><addtitle>Biochemistry</addtitle><date>2021-10-19</date><risdate>2021</risdate><volume>60</volume><issue>41</issue><spage>3098</spage><epage>3113</epage><pages>3098-3113</pages><issn>0006-2960</issn><issn>1520-4995</issn><eissn>1520-4995</eissn><abstract>The MtrCDE system confers multidrug resistance to Neisseria gonorrhoeae, the causative agent of gonorrhea. Using free and directed molecular dynamics (MD) simulations, we analyzed the interactions between MtrD and azithromycin, a transport substrate of MtrD, and a last-resort clinical treatment for multidrug-resistant gonorrhea. We then simulated the interactions between MtrD and streptomycin, an apparent nonsubstrate of MtrD. Using known conformations of MtrD homologues, we simulated a potential dynamic transport cycle of MtrD using targeted MD techniques (TMD), and we noted that forces were not applied to ligands of interest. In these TMD simulations, we observed the transport of azithromycin and the rejection of streptomycin. In an unbiased, long-time scale simulation of AZY-bound MtrD, we observed the spontaneous diffusion of azithromycin through the periplasmic cleft. Our simulations show how the peristaltic motions of the periplasmic cleft facilitate the transport of substrates by MtrD. 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| source | ACS Publications; MEDLINE |
| subjects | Azithromycin - chemistry Azithromycin - metabolism Bacterial Proteins - chemistry Bacterial Proteins - metabolism Binding Sites Biological Transport Hydrogen Bonding Ligands Membrane Proteins - chemistry Membrane Proteins - metabolism Membrane Transport Proteins - chemistry Membrane Transport Proteins - metabolism Molecular Dynamics Simulation Neisseria gonorrhoeae - chemistry Protein Binding Streptomycin - chemistry Streptomycin - metabolism |
| title | Transport Dynamics of MtrD: An RND Multidrug Efflux Pump from Neisseria gonorrhoeae |
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