Probing light chain mutation effects on thrombin via molecular dynamics simulations and machine learning

Xiao, Jiajie; Melvin, Ryan L.; Salsbury, Freddie R.

doi:10.1080/07391102.2018.1445032

Cited by 20 publications

(39 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The clustering analysis (Figure ) for catalytic pocket shows us that there is little change in cluster occupancy due to mutation. This is consistent with our previous work that the principle conformation effects of mutation are in the regulatory loops . ΔK9 does have an uncommon conformation (13.84%) with significant changes in the catalytic pocket relative to the wild type.…”

Section: Resultssupporting

confidence: 92%

“…Some typical wells, whose structures are visualized in Figures and , are labeled. In our previous study, we’ve already discussed the influence of the Na + binding on WT and ΔK9 . So in this Article, we will focus on E8K and R4A.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous studies , suggest the possible existence of two Na + binding modesthe structurally determined outer binding mode and the computationally , and experimentally implied inner binding mode. To explore the different influence of the two binding modes on thrombin, we analyze the two binding modes respectively in the Na + binding cases and find that two Na + binding modes prefer different structures of thrombin.…”

Section: Introductionmentioning

confidence: 86%

See 2 more Smart Citations

Light Chain Mutation Effects on the Dynamics of Thrombin

Xiao

Salsbury

2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Thrombin plays an important role in the process of hemostasis and blood coagulation. Studies in thrombin can help us find ways to treat cancer because thrombin is able to reduce the characteristic hypercoagulability of cancer. Thrombin is composed of two chains, the light chain and the heavy chain. The function of the heavy chain has been largely explored, while the function of the light chain was obscured until several disease-associated mutations in the light chain come to light. In this study, we want to explore the dynamic and conformation effects of mutations on the light chain further to determine possible associations between mutation, conformational changes, and disease. The study, which is a follow-up for our studies on apo thrombin and the mutant, ΔK9, mainly focuses on the mutants E8K and R4A. E8K is a diseaseassociated mutation, and R4A is used to study the role of Arg4, which is suggested experimentally to play a critical role for thrombin's catalytic activities. We performed five all-atom one microsecond-scale molecular dynamics (MD) simulations for both E8K and R4A, and quantified the changes in the conformational ensemble of the mutants. From the root-mean-square fluctuations (RMSF) for the α-carbons, we find that the atomic fluctuations change in the mutants in the 60s loop and γ loop. The correlation coefficients for the α-carbons indicate that the correlation relation for atom-pairs in the protein is also impacted. The clustering analysis and the principal component analysis (PCA) consistently tell us that the catalytic pocket and the regulatory loops are destabilized by the mutations. We also find that there are two binding modes for Na + by clustering the vector difference between the Na + ions and the 220s loop. After further analysis, we find that there is a relation between the Na + binding and the rigidification of the γ loop, which may shed light on the mysterious role of the γ loop in thrombin.

show abstract

Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 86%

See 1 more Smart Citation

Light Chain Mutation Effects on the Dynamics of Thrombin

Xiao

Salsbury

2021

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…MD simulations have also provided interesting insights into the effect produced by the binding of monovalent cations, such as Li + , Na + , and Cs + , on the protein structure/function [ 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. Moreover, several MD studies have been focused on the role of the flexibility on the substrate/inhibitor binding at the active site [ 141 , 142 , 143 ], on the structural impact of thrombin mutations [ 140 , 144 ], and on the structural basis of the aptamer recognition [ 145 , 146 , 147 ].…”

Section: Beyond a Static View Of Thrombin: Functional And Structural Evidence Of Exosite Communicationmentioning

confidence: 99%

Exosite Binding in Thrombin: A Global Structural/Dynamic Overview of Complexes with Aptamers and Other Ligands

Troisi

Balasco

Autiero

et al. 2021

IJMS

View full text Add to dashboard Cite

Thrombin is the key enzyme of the entire hemostatic process since it is able to exert both procoagulant and anticoagulant functions; therefore, it represents an attractive target for the developments of biomolecules with therapeutic potential. Thrombin can perform its many functional activities because of its ability to recognize a wide variety of substrates, inhibitors, and cofactors. These molecules frequently are bound to positively charged regions on the surface of protein called exosites. In this review, we carried out extensive analyses of the structural determinants of thrombin partnerships by surveying literature data as well as the structural content of the Protein Data Bank (PDB). In particular, we used the information collected on functional, natural, and synthetic molecular ligands to define the anatomy of the exosites and to quantify the interface area between thrombin and exosite ligands. In this framework, we reviewed in detail the specificity of thrombin binding to aptamers, a class of compounds with intriguing pharmaceutical properties. Although these compounds anchor to protein using conservative patterns on its surface, the present analysis highlights some interesting peculiarities. Moreover, the impact of thrombin binding aptamers in the elucidation of the cross-talk between the two distant exosites is illustrated. Collectively, the data and the work here reviewed may provide insights into the design of novel thrombin inhibitors.

show abstract

“…1 Therefore, thrombin is considered as a critical serine protease in the blood coagulation process. 2 In general, thrombin consists of a 36-residue light chain and a 259-residue heavy chain that can be mainly divided into the active site, exosite 1 and exosite 2, which are the regions where thrombin exerts its coagulation function. 3,4 The thrombin active site cutting brinogen into brin is located in the gap formed at the interface of the two barrels.…”

Section: Introductionmentioning

confidence: 99%