Uncovering Membrane-Bound Models of Coagulation Factors by Combined Experimental and Computational Approaches

Abstract

In the life sciences, including hemostasis and thrombosis, methods of structural biology have become indispensable tools for shedding light on underlying mechanisms that govern complex biological processes. Advancements of the relatively young field of computational biology have matured to a point where it is increasingly recognized as trustworthy and useful, in part due to their high space–time resolution that is unparalleled by most experimental techniques to date. In concert with biochemical and biophysical approaches, computational studies have therefore proven time and again in recent years to be key assets in building or suggesting structural models for membrane-bound forms of coagulation factors and their supramolecular complexes on membrane surfaces where they are activated. Such endeavors and the proposed models arising from them are of fundamental importance in describing and understanding the molecular basis of hemostasis under both health and disease conditions. We summarize the body of work done in this important area of research to drive forward both experimental and computational studies toward new discoveries and potential future therapeutic strategies.

Elucidating the complex membrane binding of a protein with multiple anchoring domains using extHMMM

“…The established binding seems equivalent to that suggested in the “Martinsried-1999” model [ 27 ] based on the X-tal structure of FV-C2, the “Milano-2006” model [ 28 ] based on FV-C2 bound to PE membrane, the “Rochester-2013” model [ 39 ] with a significantly slanted FVIIIa measured by FRET, and the “Måløv-2015” model [ 33 ] from molecular dynamics simulation (we adopt the model notation of our recent review article, Ref. [ 36 ]). The predicted hydrogen-bond interactions inside the major PS-binding site of the “Martinsried-1999” model [ 27 ] (Fig 5A in Ref.…”

Dynamic Nature ofStaphylococcus aureusType I Signal Peptidases

“…53,54 In addition, the membrane environment may likely play a role in affecting the protein localization, molecular orientation, and functions through various mechanisms (e.g., by an allosteric effect). 53,55,56 Indeed, it has been shown that phospholipids and the detergent Triton X-100 can increase the activity of truncated SpsB lacking TMD. 57,58 We therefore explored the TMD interaction with the membrane, protein's domain-domain bending in the membrane, known to have functional consequences for some proteins, 59,60 as well as the detailed interaction between the ECD and the membrane.…”

Optimizing Coarse-Grained Models for Large-Scale Membrane Protein Simulation

“…2 Computational simulation techniques such as molecular dynamics (MD) are increasingly trustworthy and useful in studying membrane proteins, in part due to their high space-time resolution. [3][4][5][6] However, using MD simulations at atomic resolution or near-atomic resolution (e.g., united atom 7,8 or MARTINI models 9 ) to simulate cellular processes involving membrane proteins at micron scale that occur extremely slowly (compared to the integration time step, which is typically a couple of femtoseconds) has not generally been feasible. Highly coarse-grained (CG) approaches, where significantly more than 4 heavy atoms and associated hydrogens maps into a single CG bead (approximately the MARTINI model resolution 9 ), is one way to overcome limitations of scale when the atomistic detail is less relevant to the question under investigation.…”