Ion Transport, Selectivity, and Electronic Polarization in Fluoride Channels

Fluoride channels (Fluc) export toxic F- from the cytoplasm. Crystallography and mutagenesis have identified several conserved residues crucial for fluoride transport, but the transport mechanism at the molecular level has remained elusive. Herein we have applied constant-pH molecular dynamics and free energy sampling methods to investigate fluoride transfer through a Fluc protein from Escherichia coli. We find that fluoride is facile to transfer in its charged form, i.e., F-, by traversing through a non-bonded network. The extraordinary F- selectivity is gained by the hydrogen-bonding capability of the central binding site and the Coulombic filter at the channel entrance. The F- transfer rate calculated using an electronically polarizable force field is significantly more accurate compared to the experimental value than that calculated using a more standard additive force field, suggesting an essential role for electronic polarization in the F- - Fluc interactions.

Download Full-text

A fragment-based approach to evaluate the performance of AMOEBA polarizable force field on charge-carrier electronic polarization

Chemical Physics ◽

10.1016/j.chemphys.2018.08.027 ◽

2019 ◽

Vol 516 ◽

pp. 84-91 ◽

Cited By ~ 1

Author(s):

Xiaobo Zhao ◽

Tao Xu ◽

Shiwei Yin

Keyword(s):

Charge Carrier ◽

Force Field ◽

Electronic Polarization ◽

Polarizable Force Field

Download Full-text

OPEP6: A New Constant-pH Molecular Dynamics Simulation Scheme with OPEP Coarse-Grained Force Field

Journal of Chemical Theory and Computation ◽

10.1021/acs.jctc.9b00202 ◽

2019 ◽

Vol 15 (6) ◽

pp. 3875-3888 ◽

Cited By ~ 7

Author(s):

Fernando Luís Barroso da Silva ◽

Fabio Sterpone ◽

Philippe Derreumaux

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Force Field ◽

Dynamics Simulation ◽

Coarse Grained ◽

Constant Ph ◽

Constant Ph Molecular Dynamics ◽

Simulation Scheme

Download Full-text

Electronic Polarization Effects upon Charge Injection in Oligoacene Molecular Crystals: Description via a Polarizable Force Field

The Journal of Physical Chemistry C ◽

10.1021/jp402991z ◽

2013 ◽

Vol 117 (27) ◽

pp. 13853-13860 ◽

Cited By ~ 42

Author(s):

Sean M. Ryno ◽

Stephen R. Lee ◽

John S. Sears ◽

Chad Risko ◽

Jean-Luc Brédas

Keyword(s):

Force Field ◽

Molecular Crystals ◽

Charge Injection ◽

Electronic Polarization ◽

Polarizable Force Field ◽

Polarization Effects

Download Full-text

Constant pH Molecular Dynamics Reveals How Proton Release Drives the Conformational Transition of a Transmembrane Efflux Pump

10.26434/chemrxiv.5496907 ◽

2017 ◽

Author(s):

Jana Shen ◽

Zhi Yue ◽

Helen Zgurskaya ◽

Wei Chen

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Transmembrane Domain ◽

Conformational Transition ◽

Conformational Dynamics ◽

Proton Release ◽

Intrinsic Resistance ◽

Constant Ph ◽

Wide Range ◽

Constant Ph Molecular Dynamics

AcrB is the inner-membrane transporter of E. coli AcrAB-TolC tripartite efflux complex, which plays a major role in the intrinsic resistance to clinically important antibiotics. AcrB pumps a wide range of toxic substrates by utilizing the proton gradient between periplasm and cytoplasm. Crystal structures of AcrB revealed three distinct conformational states of the transport cycle, substrate access, binding and extrusion, or loose (L), tight (T) and open (O) states. However, the specific residue(s) responsible for proton binding/release and the mechanism of proton-coupled conformational cycling remain controversial. Here we use the newly developed membrane hybrid-solvent continuous constant pH molecular dynamics technique to explore the protonation states and conformational dynamics of the transmembrane domain of AcrB. Simulations show that both Asp407 and Asp408 are deprotonated in the L/T states, while only Asp408 is protonated in the O state. Remarkably, release of a proton from Asp408 in the O state results in large conformational changes, such as the lateral and vertical movement of transmembrane helices as well as the salt-bridge formation between Asp408 and Lys940 and other sidechain rearrangements among essential residues.Consistent with the crystallographic differences between the O and L protomers, simulations offer dynamic details of how proton release drives the O-to-L transition in AcrB and address the controversy regarding the proton/drug stoichiometry. This work offers a significant step towards characterizing the complete cycle of proton-coupled drug transport in AcrB and further validates the membrane hybrid-solvent CpHMD technique for studies of proton-coupled transmembrane proteins which are currently poorly understood. <p><br></p>

Download Full-text

Recent development and application of constant pH molecular dynamics

Molecular Simulation ◽

10.1080/08927022.2014.907492 ◽

2014 ◽

Vol 40 (10-11) ◽

pp. 830-838 ◽

Cited By ~ 54

Author(s):

Wei Chen ◽

Brian H. Morrow ◽

Chuanyin Shi ◽

Jana K. Shen

Keyword(s):

Molecular Dynamics ◽

Constant Ph ◽

Constant Ph Molecular Dynamics

Download Full-text

On the Use of the Discrete Constant pH Molecular Dynamics to Describe the Conformational Space of Peptides

Polymers ◽

10.3390/polym13010099 ◽

2020 ◽

Vol 13 (1) ◽

pp. 99

Author(s):

Cristian Privat ◽

Sergio Madurga ◽

Francesc Mas ◽

Jaime Rubio-Martínez

Keyword(s):

Molecular Dynamics ◽

Amino Acids ◽

Md Simulations ◽

Point Of View ◽

Conformational Space ◽

Conformational Sampling ◽

Protonation State ◽

Constant Ph ◽

Biochemical Systems ◽

Constant Ph Molecular Dynamics

Solvent pH is an important property that defines the protonation state of the amino acids and, therefore, modulates the interactions and the conformational space of the biochemical systems. Generally, this thermodynamic variable is poorly considered in Molecular Dynamics (MD) simulations. Fortunately, this lack has been overcome by means of the Constant pH Molecular Dynamics (CPHMD) methods in the recent decades. Several studies have reported promising results from these approaches that include pH in simulations but focus on the prediction of the effective pKa of the amino acids. In this work, we want to shed some light on the CPHMD method and its implementation in the AMBER suitcase from a conformational point of view. To achieve this goal, we performed CPHMD and conventional MD (CMD) simulations of six protonatable amino acids in a blocked tripeptide structure to compare the conformational sampling and energy distributions of both methods. The results reveal strengths and weaknesses of the CPHMD method in the implementation of AMBER18 version. The change of the protonation state according to the chemical environment is presumably an improvement in the accuracy of the simulations. However, the simulations of the deprotonated forms are not consistent, which is related to an inaccurate assignment of the partial charges of the backbone atoms in the CPHMD residues. Therefore, we recommend the CPHMD methods of AMBER program but pointing out the need to compare structural properties with experimental data to bring reliability to the conformational sampling of the simulations.

Download Full-text

Anti-TNF Alpha Antibody Humira with pH-dependent Binding Characteristics: A constant-pH Molecular Dynamics, Gaussian Accelerated Molecular Dynamics, and In Vitro Study

Biomolecules ◽

10.3390/biom11020334 ◽

2021 ◽

Vol 11 (2) ◽

pp. 334

Author(s):

Shih-Ting Hong ◽

Yu-Cheng Su ◽

Yu-Jen Wang ◽

Tian-Lu Cheng ◽

Yeng-Tseng Wang

Keyword(s):

Molecular Dynamics ◽

Tnf Alpha ◽

Complex Structures ◽

Binding Characteristics ◽

Accelerated Molecular Dynamics ◽

Constant Ph ◽

Ph Dependent ◽

Constant Ph Molecular Dynamics ◽

Antibody Drug

Humira is a monoclonal antibody that binds to TNF alpha, inactivates TNF alpha receptors, and inhibits inflammation. Neonatal Fc receptors can mediate the transcytosis of Humira–TNF alpha complex structures and process them toward degradation pathways, which reduces the therapeutic effect of Humira. Allowing the Humira–TNF alpha complex structures to dissociate to Humira and soluble TNF alpha in the early endosome to enable Humira recycling is crucial. We used the cytoplasmic pH (7.4), the early endosomal pH (6.0), and pKa of histidine side chains (6.0–6.4) to mutate the residues of complementarity-determining regions with histidine. Our engineered Humira (W1-Humira) can bind to TNF alpha in plasma at neutral pH and dissociate from the TNF alpha in the endosome at acidic pH. We used the constant-pH molecular dynamics, Gaussian accelerated molecular dynamics, two-dimensional potential mean force profiles, and in vitro methods to investigate the characteristics of W1-Humira. Our results revealed that the proposed Humira can bind TNF alpha with pH-dependent affinity in vitro. The W1-Humira was weaker than wild-type Humira at neutral pH in vitro, and our prediction results were close to the in vitro results. Furthermore, our approach displayed a high accuracy in antibody pH-dependent binding characteristics prediction, which may facilitate antibody drug design. Advancements in computational methods and computing power may further aid in addressing the challenges in antibody drug design.

Download Full-text