Importance of the Force Field Choice in Capturing Functionally Relevant Dynamics in the von Willebrand Factor

Abstract

Whether recent updates and new releases of atomistic force fields can model the structural and dynamical properties of proteins containing both folded and partially disordered domains is still unclear. To address this fundamental question, we tested eight recently released force fields against our set of nuclear magnetic resonance (NMR) observables for a complex and medically relevant system, the major factor VIII binding region on the von Willebrand factor. This biomedically important region comprises both a folded and a partially structured domain. By using an enhanced sampling technique (temperature replica-exchange molecular dynamics simulations), we find that some force fields indeed rise to the challenge and capture the structural and dynamical features of the NMR ensemble and, therefore, are the appropriate choice for simulations of proteins with partially structured domains. What is more, we show that only such force fields can qualitatively capture the effects of a pathogenic mutation on the structural ensemble.

Atomic Partitioning of the MPn (n= 2, 3, 4) Dynamic Electron Correlation Energy by the Interacting Quantum Atoms Method: A Fast and Accurate Electrostatic Potential Integral Approach

“…Atomistic force fields continue to be developed given their growing use and impact in biological and materials science. Extensive comparisons between, traditional force fields can offer guidance in this development, as well as comparisons between machine‐learnt potentials. Within this grand scheme of force field development, the modeling of dispersion energy has received special attention over the last decade and more.…”

Improved Modeling of Peptide-Protein Binding through Global Docking and Accelerated Molecular Dynamics Simulations

“…CHARMM36) and solvent models (e.g., TIP4P and implicit solvent, etc.) (Kuzmanic et al, 2019) are to be further investigated. Development of novel protocols to increase the accuracy of peptide-protein structural prediction will facilitate peptide drug design.…”

Recent development of atomistic force fields and simulations of intrinsically disordered proteins

“…Piana等 [28] 对a99SB-disp力场的非键和二面角参数进行 [13] (网络版彩图) [48,49] 、肿瘤抑制因子p53的转 录激活结构域(p53-TAD) [50] 和von Willebrand因子 (VWF)的TIL′E′区域 [51] , 折叠蛋白体系包括泛素、 GB3蛋白 [52] 和肌联蛋白I91结构域(titin I91) [53] . 、24个氨 基酸的Histatin5 [55] .…”