scholarly journals How proteins open fusion pores: insights from molecular simulations

2020 ◽  
Author(s):  
H. Jelger Risselada ◽  
Helmut Grubmüller
Keyword(s):  
Free Energy ◽  
Fusion Proteins ◽  
Graphics Processing Units ◽  
Fusion Reaction ◽  
Molecular Simulations ◽  
Minimum Free Energy ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Fusion Pore ◽  
Graphics Processing

AbstractFusion proteins can play a versatile and involved role during all stages of the fusion reaction. Their roles go far beyond forcing the opposing membranes into close proximity to drive stalk formation and fusion. Molecular simulations have played a central role in providing a molecular understanding of how fusion proteins actively overcome the free energy barriers of the fusion reaction up to the expansion of the fusion pore. Unexpectedly, molecular simulations have revealed a preference of the biological fusion reaction to proceed through asymmetric pathways resulting in the formation of, e.g., a stalk-hole complex, rim-pore, or vertex pore. Force-field based molecular simulations are now able to directly resolve the minimum free-energy path in protein-mediated fusion as well as quantifying the free energies of formed reaction intermediates. Ongoing developments in Graphics Processing Units (GPUs), free energy calculations, and coarse-grained force-fields will soon gain additional insights into the diverse roles of fusion proteins.

scholarly journals Thermodynamically reversible paths of the first fusion intermediate reveal an important role for membrane anchors of fusion proteins

2019 ◽  
Vol 116 (7) ◽  
pp. 2571-2576 ◽  
Author(s):  
Yuliya G. Smirnova ◽  
Herre Jelger Risselada ◽  
Marcus Müller
Keyword(s):  
Free Energy ◽  
Fusion Proteins ◽  
Biological Membrane ◽  
Fusion Reaction ◽  
Molecular Shape ◽  
Minimum Free Energy ◽  
Spontaneous Curvature ◽  
Free Energy Barrier ◽  
Lipid Species ◽  
Dynamics Simulations

Biological membrane fusion proceeds via an essential topological transition of the two membranes involved. Known players such as certain lipid species and fusion proteins are generally believed to alter the free energy and thus the rate of the fusion reaction. Quantifying these effects by theory poses a major challenge since the essential reaction intermediates are collective, diffusive and of a molecular length scale. We conducted molecular dynamics simulations in conjunction with a state-of-the-art string method to resolve the minimum free-energy path of the first fusion intermediate state, the so-called stalk. We demonstrate that the isolated transmembrane domains (TMDs) of fusion proteins such as SNARE molecules drastically lower the free energy of both the stalk barrier and metastable stalk, which is not trivially explained by molecular shape arguments. We relate this effect to the local thinning of the membrane (negative hydrophobic mismatch) imposed by the TMDs which favors the nearby presence of the highly bent stalk structure or prestalk dimple. The distance between the membranes is the most crucial determinant of the free energy of the stalk, whereas the free-energy barrier changes only slightly. Surprisingly, fusion enhancing lipids, i.e., lipids with a negative spontaneous curvature, such as PE lipids have little effect on the free energy of the stalk barrier, likely because of its single molecular nature. In contrast, the lipid shape plays a crucial role in overcoming the hydration repulsion between two membranes and thus rather lowers the total work required to form a stalk.

scholarly journals SNAREs, tethers and SM proteins: how to overcome the final barriers to membrane fusion?

2020 ◽  
Vol 477 (1) ◽  
pp. 243-258 ◽  
Author(s):  
Herre Jelger Risselada ◽  
Andreas Mayer
Keyword(s):  
Free Energy ◽  
Membrane Fusion ◽  
Fusion Proteins ◽  
Fusion Reaction ◽  
Natural Resistance ◽  
Fusion Pore ◽  
Viral Fusion ◽  
Protein Fusion ◽  
Energy Barriers ◽  
Sm Proteins

Physiological membrane vesicles are built to separate reaction spaces in a stable manner, even when they accidentally collide or are kept in apposition by spatial constraints in the cell. This requires a natural resistance to fusion and mixing of their content, which originates from substantial energetic barriers to membrane fusion [1]. To facilitate intracellular membrane fusion reactions in a controlled manner, proteinaceous fusion machineries have evolved. An important open question is whether protein fusion machineries actively pull the fusion reaction over the present free energy barriers, or whether they rather catalyze fusion by lowering those barriers. At first sight, fusion proteins such as SNARE complexes and viral fusion proteins appear to act as nano-machines, which mechanically transduce force to the membranes and thereby overcome the free energy barriers [2,3]. Whether fusion proteins additionally alter the free energy landscape of the fusion reaction via catalytic roles is less obvious. This is a question that we shall discuss in this review, with particular focus on the influence of the eukaryotic SNARE-dependent fusion machinery on the final step of the reaction, the formation and expansion of the fusion pore.

Self-assembly of coarse-grained ionic surfactants accelerated by graphics processing units

Soft Matter ◽  
2012 ◽  
Vol 8 (8) ◽  
pp. 2385-2397 ◽  
Author(s):  
David N. LeBard ◽  
Benjamin G. Levine ◽  
Philipp Mertmann ◽  
Stephen A. Barr ◽  
Arben Jusufi ◽  
...  
Keyword(s):  
Self Assembly ◽  
Graphics Processing Units ◽  
Coarse Grained ◽  
Ionic Surfactants ◽  
Graphics Processing

scholarly journals Molecular stripping in theNF-κB/IκB/DNAgenetic regulatory network

2015 ◽  
Vol 113 (1) ◽  
pp. 110-115 ◽  
Author(s):  
Davit A. Potoyan ◽  
Weihua Zheng ◽  
Elizabeth A. Komives ◽  
Peter G. Wolynes
Keyword(s):  
Free Energy ◽  
Transcription Factor ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Genetic Switch ◽  
Binary And Ternary Complexes ◽  
Landscape Models ◽  
Gene Switches ◽  
Dna Release ◽  
Dynamics Simulations

Genetic switches based on theNF-κB/IκB/DNAsystem are master regulators of an array of cellular responses. Recent kinetic experiments have shown thatIκBcan actively removeNF-κBbound to its genetic sites via a process called “molecular stripping.” This allows theNF-κB/IκB/DNAswitch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse-grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factorNF-κBand its various binary and ternary complexes with DNA and the inhibitorIκB. These studies show that the function of theNF-κB/IκB/DNAgenetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding ofIκBthat occurs through conformational selection. Free energy calculations for DNA binding show that the binding ofIκBnot only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.

scholarly journals Interaction of lecithin-cholesterol acyltransferase with lipid surfaces and apolipoprotein A-I derived peptides: implications for the cofactor mechanism of apolipoprotein A-I

2017 ◽  
Author(s):  
Marco G. Casteleijn ◽  
Petteri Parkkila ◽  
Tapani Viitala ◽  
Artturi Koivuniemi
Keyword(s):  
Amino Acids ◽  
Free Energy ◽  
Active Site ◽  
Cholesterol Acyltransferase ◽  
Lipid Binding ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Lecithin Cholesterol Acyltransferase ◽  
Apolipoprotein A ◽  
Lipid Surface

AbstractLecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for the formation of cholesteryl esters from cholesterol (CHOL) and phospholipid (PL) molecules in high-density lipoprotein (HDL) particles that play a crucial role in the reverse cholesterol transport and the development of coronary heart disease (CHD). However, it is poorly understood how LCAT interacts with lipoprotein surfaces and how apolipoprotein A-I (apoA-I) activates it. Thus, here we have studied the interactions between LCAT and lipids through extensive atomistic and coarse-grained molecular dynamics simulations to reveal mechanistic details behind the cholesterol esterification process catalyzed by LCAT. In addition, we studied the binding of LCAT to apoA-I derived peptides, and their effect on LCAT lipid association utilizing experimental surface sensitive biophysical methods. Our simulations show that LCAT anchors itself to lipoprotein surfaces by utilizing non-polar amino acids located in the membrane-binding domain and the active site tunnel opening. Meanwhile, the membrane anchoring hydrophobic amino acids attract cholesterol molecules next to them. The results also highlight the role of the lid-loop in the lipid binding and conformation of LCAT with respect to the lipid surface. The apoA-I derived peptides from the LCAT activating region bind to LCAT and promote its lipid surface interactions, although some of these peptides do not bind lipids individually. By means of free-energy calculations we provided a hypothetical explanation for this mechanism. We also found that the transfer free-energy of PL to the active site is consistent with the activation energy of LCAT. Furthermore, the entry of CHOL molecules into the active site becomes highly favorable by the acylation of SER181. The results provide substantial mechanistic insights concerning the activity of LCAT that may lead to the development of novel pharmacological agents preventing CHD in the future.

In-silico Methods of Drug Design: Molecular Simulations and Free Energy Calculations

2019 ◽  
pp. 521-533 ◽  
Author(s):  
Fortunatus Chidolue Ezebuo ◽  
Prem P. Kushwaha ◽  
Atul K. Singh ◽  
Shashank Kumar ◽  
Pushpendra Singh
Keyword(s):  
Free Energy ◽  
Drug Design ◽  
In Silico ◽  
Molecular Simulations ◽  
Free Energy Calculations ◽  
Energy Calculations ◽  
In Silico Methods

scholarly journals Molecular stripping in the NFκB/IκB/DNA genetic regulatory network

2015 ◽  
Author(s):  
Davit Potoyan ◽  
Weihua Zheng ◽  
Elizabeth Komives ◽  
Peter Wolynes
Keyword(s):  
Free Energy ◽  
Transcription Factor ◽  
Free Energy Calculations ◽  
Coarse Grained ◽  
Genetic Switch ◽  
Binary And Ternary Complexes ◽  
Landscape Models ◽  
Gene Switches ◽  
Dna Release ◽  
Dynamics Simulations

Genetic switches based on the NFκB/IκB/DNA system are master regulators of an array of cellular responses. Recent kinetic experiments have shown that IκB can actively remove NFκB bound to its genetic sites via a process called "molecular stripping". This allows the NFκB/IκB/DNA switch to function under kinetic control rather than the thermodynamic control contemplated in the traditional models of gene switches. Using molecular dynamics simulations of coarse grained predictive energy landscape models for the constituent proteins by themselves and interacting with the DNA we explore the functional motions of the transcription factor NFκB and its various binary and ternary complexes with DNA and the inhibitor IκB. These studies show that the function of the NFκB/IκB/DNA genetic switch is realized via an allosteric mechanism. Molecular stripping occurs through the activation of a domain twist mode by the binding of IkB which occurs through conformational selection. Free energy calculations for DNA binding show that the binding of IκB not only results in a significant decrease of the affinity of the transcription factor for the DNA but also kinetically speeds DNA release. Projections of the free energy onto various reaction coordinates reveal the structural details of the stripping pathways.

scholarly journals Energetics and Conformational Pathways of Functional Rotation in the Multidrug Transporter AcrB

2017 ◽  
Author(s):  
Yasuhiro Matsunaga ◽  
Tsutomu Yamane ◽  
Tohru Terada ◽  
Kei Moritsugu ◽  
Hiroshi Fujisaki ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Transport ◽  
Proton Translocation ◽  
Minimum Free Energy ◽  
Proton Motive Force ◽  
Free Energy Calculations ◽  
Vertical Shear ◽  
Multidrug Transporter ◽  
Simulation Studies ◽  
Transmembrane Helices

The multidrug transporter AcrB transports a broad range of drugs out of the cell by means of the proton-motive force. The asymmetric crystal structure of trimeric AcrB suggests a functionally rotating mechanism for drug transport. Despite various supportive evidences from biochemical and simulation studies for this mechanism, the link between the functional rotation and proton translocation across the membrane remains elusive. Here, calculating the minimum free energy pathway of the functional rotation for the complete AcrB trimer, we describe the structural and energetic basis behind the coupling between the functional rotation and the proton translocation at atomic-level. Free energy calculations show that protonation of Asp408 in the transmembrane portion of the drug-bound protomer drives the functional rotation. The conformational pathway identifies vertical shear motions among several transmembrane helices, which regulates alternate access of water in the transmembrane as well as peristaltic motions pumping drugs in the periplasm.

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