Selective enhanced sampling in dihedral energy facilitates overcoming the dihedral energy increase in protein folding and accelerates the searching for protein native structure

2019 ◽  
Vol 21 (20) ◽  
pp. 10423-10435 ◽  
Author(s):  
Qiang Shao ◽  
Lijiang Yang ◽  
Weiliang Zhu
Keyword(s):  
Protein Folding ◽  
Sampling Method ◽  
Folding Pathway ◽  
Enhanced Sampling ◽  
Native Structure ◽  
Energy Increase ◽  
Folded Structure

A dihedral-energy-based selective enhanced sampling method (D-SITSMD) is presented with improved capabilities for searching a protein's natively folded structure and for providing the underlying folding pathway.

scholarly journals A protein folding intermediate pulls its weight

2020 ◽  
Vol 295 (33) ◽  
pp. 11418-11419
Author(s):  
Jonathan P. Schlebach
Keyword(s):  
Protein Folding ◽  
Protein Synthesis ◽  
Rnase H ◽  
Biased Sampling ◽  
Folding Pathway ◽  
Folding Intermediate ◽  
Native Structure ◽  
Unfolded Proteins ◽  
Biochemical Function ◽  
Folding Pathways

Proteins must acquire and maintain a specific fold to execute their biochemical function(s). In solution, unfolded proteins typically find this native structure through a biased sampling of preferred intermediate conformations. However, the initial search for these structures begins during protein synthesis, and it is unclear how much interactions between the ribosome and nascent polypeptide skew folding pathways. In this issue, Jensen and colleagues use a ribosomal force–profiling assay to show that RNase H forms a similar folding intermediate on and off the ribosome. In conjunction with measurements of the rate of RNase H unfolding on and off the ribosome, their results show that ribosomal interactions have little impact on the folding pathway of RNase H. These findings suggest that the ribosome itself does not necessarily rewire protein folding reactions.

scholarly journals Synthesis runs counter to directional folding of a nascent protein domain

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Xiuqi Chen ◽  
Nandakumar Rajasekaran ◽  
Kaixian Liu ◽  
Christian M. Kaiser
Keyword(s):  
Single Molecule ◽  
Molten Globule ◽  
Elongation Factor ◽  
Protein Domain ◽  
Folding Pathway ◽  
Native Structure ◽  
Folding Intermediates ◽  
C Terminus

Abstract Folding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.

scholarly journals Synthesis runs counter to directional folding of a nascent protein domain

2020 ◽  
Author(s):  
Xiuqi Chen ◽  
Nandakumar Rajasekaran ◽  
Kaixian Liu ◽  
Christian M. Kaiser
Keyword(s):  
Single Molecule ◽  
Molten Globule ◽  
Elongation Factor ◽  
Protein Domain ◽  
Folding Pathway ◽  
Native Structure ◽  
Folding Intermediates ◽  
C Terminus

AbstractFolding of individual domains in large proteins during translation helps to avoid otherwise prevalent inter-domain misfolding. How folding intermediates observed in vitro for the majority of proteins relate to co-translational folding remains unclear. Combining in vivo and single-molecule experiments, we followed the co-translational folding of the G-domain, encompassing the first 293 amino acids of elongation factor G. Surprisingly, the domain remains unfolded until it is fully synthesized, without collapsing into molten globule-like states or forming stable intermediates. Upon fully emerging from the ribosome, the G-domain transitions to its stable native structure via folding intermediates. Our results suggest a strictly sequential folding pathway initiating from the C-terminus. Folding and synthesis thus proceed in opposite directions. The folding mechanism is likely imposed by the final structure and might have evolved to ensure efficient, timely folding of a highly abundant and essential protein.

scholarly journals Thermosensitive PBP2a requires extracellular folding factors PrsA and HtrA1 for Staphylococcus aureus MRSA β-lactam resistance

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Mélanie Roch ◽  
Emmanuelle Lelong ◽  
Olesya O. Panasenko ◽  
Roberto Sierra ◽  
Adriana Renzoni ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Protein Folding ◽  
Antibiotic Resistance ◽  
Active Site ◽  
Complete Loss ◽  
Folding Pathway ◽  
Human Pathogen ◽  
Clinical Challenge ◽  
Aggregation Activity ◽  
Horizontal Acquisition

AbstractStaphylococcus aureus is a major human pathogen and represents a clinical challenge because of widespread antibiotic resistance. Methicillin resistant Staphylococcus aureus (MRSA) is particularly problematic and originates by the horizontal acquisition of mecA encoding PBP2a, an extracellular membrane anchored transpeptidase, which confers resistance to β-lactam antibiotics by allosteric gating of its active site channel. Herein, we show that dual disruption of PrsA, a lipoprotein chaperone displaying anti-aggregation activity, together with HtrA1, a membrane anchored chaperone/serine protease, resulted in severe and synergistic attenuation of PBP2a folding that restores sensitivity to β-lactams such as oxacillin. Purified PBP2a has a pronounced unfolding transition initiating at physiological temperatures that leads to irreversible precipitation and complete loss of activity. The concordance of genetic and biochemical data highlights the necessity for extracellular protein folding factors governing MRSA β-lactam resistance. Targeting the PBP2a folding pathway represents a particularly attractive adjuvant strategy to combat antibiotic resistance.

Assessing the performance of the MM/PBSA and MM/GBSA methods. 10. Impacts of enhanced sampling and variable dielectric model on protein–protein Interactions

2019 ◽  
Vol 21 (35) ◽  
pp. 18958-18969 ◽  
Author(s):  
Ercheng Wang ◽  
Gaoqi Weng ◽  
Huiyong Sun ◽  
Hongyan Du ◽  
Feng Zhu ◽  
...  
Keyword(s):  
Protein Folding ◽  
Protein Interactions ◽  
Conformational Transitions ◽  
Protein Recognition ◽  
Enhanced Sampling ◽  
Protein Protein Interactions ◽  
Dielectric Model

Enhanced sampling has been extensively used to capture the conformational transitions in protein folding, but it attracts much less attention in the studies of protein–protein recognition.

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