Center for Molecular Modeling - A. R. Mehdipour

Dissecting the conformational complexity and mechanism of a bacterial heme transporter

Reza — Wed, 20 Sep 2023 21:39:54 +0000

D. Wu, A. R. Mehdipour, F. Finke, H. G. Goojani, R. R. Groh, T. M. Grund, T. M. B. Reichhart, R. Zimmermann, S. Welsch, D. Bald, M. Shepherd, G. Hummer, S. Safarian

Nature Chemical Biology

19,992–1003

2023

Abstract

Iron-bound cyclic tetrapyrroles (hemes) are redox-active cofactors in bioenergetic enzymes. However, the mechanisms of heme transport and insertion into respiratory chain complexes remain unclear. Here, we used cellular, biochemical, structural and computational methods to characterize the structure and function of the heterodimeric bacterial ABC transporter CydDC. We provide multi-level evidence that CydDC is a heme transporter required for functional maturation of cytochrome bd, a pharmaceutically relevant drug target. Our systematic single-particle cryogenic-electron microscopy approach combined with atomistic molecular dynamics simulations provides detailed insight into the conformational landscape of CydDC during substrate binding and occlusion. Our simulations reveal that heme binds laterally from the membrane space to the transmembrane region of CydDC, enabled by a highly asymmetrical inward-facing CydDC conformation. During the binding process, heme propionates interact with positively charged residues on the surface and later in the substrate-binding pocket of the transporter, causing the heme orientation to rotate 180°.

Green Open Access

DOI

http://dx.doi.org/

Force-tuned avidity of spike variant-ACE2 interactions viewed on the single-molecule level

Reza — Tue, 27 Dec 2022 10:44:05 +0000

R. Zhu, D. Canena, M. Sikora, M. Klausberger, H. Seferovic, A. R. Mehdipour, L. Hain, E. Laurent, V. Monteil, G. Wirnsberger, R. Wieneke, R. Tampé, N.F. Kienzl, L. Mach, A. Mirazimi, Y. Jin Oh, J.M. Penninger, G. Hummer, P. Hinterdorfer

Nature Communications

13, 7926

2022

Abstract

Recent waves of COVID-19 correlate with the emergence of the Delta and the Omicron variant. We report that the Spike trimer acts as a highly dynamic molecular caliper, thereby forming up to three tight bonds through its RBDs with ACE2 expressed on the cell surface. The Spike of both Delta and Omicron (B.1.1.529) Variant enhance and markedly prolong viral attachment to the host cell receptor ACE2, as opposed to the early Wuhan-1 isolate. Delta Spike shows rapid binding of all three Spike RBDs to three different ACE2 molecules with considerably increased bond lifetime when compared to the reference strain, thereby significantly amplifying avidity. Intriguingly, Omicron (B.1.1.529) Spike displays less multivalent bindings to ACE2 molecules, yet with a ten time longer bond lifetime than Delta. Delta and Omicron (B.1.1.529) Spike variants enhance and prolong viral attachment to the host, which likely not only increases the rate of viral uptake, but also enhances the resistance of the variants against host-cell detachment by shear forces such as airflow, mucus or blood flow. We uncover distinct binding mechanisms and strategies at single-molecule resolution, employed by circulating SARS-CoV-2 variants to enhance infectivity and viral transmission.

DOI

http://dx.doi.org/

Private attachment

s41467-022-35641-3.pdf

Cryo-EM structures of pentameric autoinducer-2 exporter from E. coli reveal its transport mechanism

Reza — Thu, 02 Jun 2022 12:07:47 +0000

R. Khera, A. R. Mehdipour, J.R. Bolla, J. Kahnt, S. Welsch, U. Ermler, C. Muenke, C.V. Robinson, G. Hummer, H. Xie, H. Michel

EMBO Journal

41, 18, e109990

2022

Abstract

Bacteria utilize small extracellular molecules to communicate in order to collectively coordinate their behaviors in response to the population density. Autoinducer-2 (AI-2), a universal molecule for both intra- and inter-species communication, is involved in the regulation of biofilm formation, virulence, motility, chemotaxis and antibiotic resistance. While many studies have been devoted to understanding the biosynthesis and sensing of AI-2, very little information is available on its export. The protein TqsA from E. coli, which belongs to a large underexplored membrane transporter family, the AI-2 exporter superfamily, has been shown to export AI-2. Here, we report the cryogenic electron microscopic structures of two AI-2 exporters (TqsA and YdiK) from E. coli at 3.35 Å and 2.80 Å resolutions, respectively. Our structures suggest that the AI-2 exporter exists as a homo-pentameric complex. In silico molecular docking and native mass spectrometry experiments were employed to demonstrate the interaction between AI-2 and TqsA, and the results highlight the functional importance of two helical hairpins in substrate binding. We propose that each monomer works as an independent functional unit utilizing an elevator-type transport mechanism. This study emphasizes the structural distinctiveness of this family of pentameric transporters and provides fundamental insights for the ensuing studies.

DOI

http://dx.doi.org/

Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter

Reza — Thu, 02 Jun 2022 09:07:25 +0000

E. Lambert, A. R. Mehdipour, A. Schmidt, G. Hummer, C. Perez

Nature Communications

Volume 13, issue 1, article number 1022

2022

Abstract

Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters take part in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acid synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a ‘trap-and-flip’ mechanism that might be shared among MFS lipid transporters.

DOI

http://dx.doi.org/10.1038/s41467-022-28361-1

Private attachment

s41467-022-28361-1.pdf

Computational modeling of the mouse IL-12 receptor complex

mieke — Mon, 04 Aug 2025 10:58:16 +0000

A. M. T. Mahmoud

International Master of Science in Sustainable Drug Discovery

2025

Supervisors

Prof. Dr. Ahmad Reza Mehdipour

Artificial intelligence-driven modeling of protein complexes

leen — Thu, 06 Feb 2025 13:00:43 +0000

L. Ronsyn

Master of Science in Biochemistry and Biotechnology

2023

Supervisors

Prof. Dr. Ahmadreza Mehdipour; Prof. Karolien De Bosscher

Computational study of drug binding in multidrug efflux transporters in pathogenic bacteria

leen — Thu, 06 Feb 2025 12:51:35 +0000

S. De Ruyter

Master of Science in Drug Development

2024

Supervisors

Prof. Dr. Ahmad Reza Mehdipour

Modeling of anti-parasitic activity of nucleoside derivatives using machine learning

leen — Thu, 06 Feb 2025 12:50:36 +0000

M. Milad

International Master of Science in Sustainable Drug Discovery

2024

Supervisors

Prof. Dr. Ahmad Reza Mehdipour; Prof. Serge Van Calenbergh

Using advanced molecular dynamics simulations to unravel the drug binding into membrane proteins

leen — Tue, 04 Feb 2025 13:46:24 +0000

W. Dhondt

Master of Science in Biochemistry and Biotechnology

2024

Supervisors

Prof. Dr. Ahmadreza Mehdipour, Prof. Dr. ir. Louis Vanduyfhuys

Computational microscopy of substrate binding in lipid transporters

Reza — Thu, 22 Dec 2022 15:25:58 +0000

A. R. Mehdipour

ISBN/ISSN:

Keynote

Conference / event / venue

2nd Molecular modelling and simulation workshop

Frankfurt, Germany

Thursday, 15 December, 2022