Title: A Minimal Membrane Metal Transport System: Dynamics and Energetics of mer Proteins

Abstract

The mer operon in bacteria encodes a set of proteins and enzymes that impart resistance to environmental mercury toxicity by importing Hg²⁺ and reducing it to volatile Hg(0). Because the reduction occurs in the cytoplasm, mercuric ions must first be transported across the cytoplasmic membrane by one of a few known transporters. MerF is the smallest of these, containing only two transmembrane helices and two pairs of vicinal cysteines that coordinate mercuric ions. In this work, we use molecular dynamics simulations to characterize the dynamics of MerF in its apo and Hg²⁺-bound states. We find that the apo state positions one of the cysteine pairs closer to the periplasmic side of the membrane, while in the bound state the same pair approaches the cytoplasmic side. This finding is consistent with the functional requirement of accepting Hg²⁺ from the periplasmic space, sequestering it on acceptance, and transferring it to the cytoplasm. Conformational changes in the TM helices facilitate the functional interaction of the two cysteine pairs. Free-energy calculations provide a barrier of 16 kcal/mol for the association of the periplasmic Hg²⁺-bound protein MerP with MerF and 7 kcal/mol for the subsequent association of MerF's two cysteine pairs. Despite the significant conformationalmore » changes required to move the binding site across the membrane, coarse-grained simulations of multiple copies of MerF support the expectation that it functions as a monomer. Finally, our results demonstrate how conformational changes and binding thermodynamics could lead to such a small membrane protein acting as an ion transporter.« less

Authors:

Hwang, Hyea J. ^[1]; Hazel, Anthony  ^[2];

• Search DOE PAGES for author "Hazel, Anthony"
• Search DOE PAGES for ORCID "0000-0002-8195-7909"

Lian, Peng ^[3]; Smith, Jeremy C.  ^[3];

• Search DOE PAGES for author "Smith, Jeremy C."
• Search DOE PAGES for ORCID "0000-0002-2978-3227"

Gumbart, James C.  ^[2];

• Search DOE PAGES for author "Gumbart, James C."
• Search DOE PAGES for ORCID "0000-0002-1510-7842"

Parks, Jerry M.  ^[4]

• Search DOE PAGES for author "Parks, Jerry M."
• Search DOE PAGES for ORCID "0000-0002-3103-9333"

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+ Show Author Affiliations

1. Georgia Inst. of Technology, Atlanta, GA (United States); Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
2. Georgia Inst. of Technology, Atlanta, GA (United States)
3. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Publication Date:

Wed Nov 13 00:00:00 EST 2019

Research Org.:

Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Org.:

USDOE Office of Science (SC), Biological and Environmental Research (BER); National Institutes of Health (NIH); National Science Foundation (NSF)

OSTI Identifier:

1607025

Alternate Identifier(s):

OSTI ID: 1574067

Grant/Contract Number:  

AC05-00OR22725; SC0014664; R01-GM123169; OCI-1053575

Resource Type:

Accepted Manuscript

Journal Name:

Journal of Computational Chemistry

Additional Journal Information:

Journal Volume: 41; Journal Issue: 6; Journal ID: ISSN 0192-8651

Publisher:

Wiley

Country of Publication:

United States

Language:

English

Subject:

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; MerF; mercury transport; membrane transporter; free-energy calculations; molecular dynamics