Force Field Development for Protein Absorption Modeling

描述（由申请人提供）：由于蛋白质在种植体生物相容性中的控制作用，了解和控制蛋白质在种植体表面的吸附仍然是生物材料领域的主要研究领域之一。尽管人们非常渴望，但对蛋白质吸附如何发生以及如何控制它的分子水平的详细理解仍然缺乏。分子模拟通过提供一种准确预测和可视化分子水平行为的工具，为解决这些限制提供了巨大的潜力。然而，在实现这一潜力之前，必须专门为此应用程序开发方法。因此，拟议的R01研究计划的总体目标是开发分子模拟能力，以准确模拟蛋白质在表面上的吸附，最初具有类似聚合物的功能。这将通过首先修改完善的CHARMM分子模拟程序来实现，以便在同一模拟中使用两种不同的力场（I类或II类）来分别表示溶液相和固相。这将使吸附系统的两个阶段能够通过专门针对特定材料系统（例如，水溶液中的蛋白质与结晶聚合物）开发和验证的力场精确建模。然而，两个阶段之间的接口必须分别进行调优和验证。为了实现这一目标，将使用表面等离子体共振光谱进行实验吸附研究，使用设计的主-客肽系统来生成实验吸附数据，这些数据将用于评估、调整和验证CHARMM界面力场，以准确模拟蛋白质在固-液界面的吸附行为。一旦验证，混合力场系统将用于模拟生物医学相关蛋白质在功能化表面上的吸附行为，并将结果与一组匹配的实验研究进行定量比较，以证明开发的准确模拟蛋白质吸附行为的能力。这些模拟能力的成功开发将为分子模拟的建立奠定基础，作为生物材料界在分子水平上研究和控制蛋白质吸附行为的有价值的表面设计工具，并直接应用于医疗器械设计，以提高植入物的生物相容性，改善患者护理。

DESCRIPTION (provided by applicant): Because of its governing role in implant biocompatibility, the understanding and control of protein adsorption to implant surfaces continues to be one of the major areas of research in the field of biomaterials. Although greatly desired, a detailed molecular-level understanding of how protein adsorption occurs, and how to control it, are still lacking. Molecular simulation offers great potential to help address these limitations by providing a tool to accurately predict and visualize molecular-level behavior. However, before this potential can be realized, methods must be specifically developed for this application. The overall objective of the proposed R01 research program is therefore to develop molecular simulation capabilities to accurately simulate protein adsorption on surfaces, initially with polymer-like functionality . This will be accomplished by first modifying the well-established CHARMM molecular simulation program to enable two different force fields (either Class I or II type) to be used in the same simulation to separately represent the solution phase and the solid phase. This will enable both phases of an adsorption system to be accurately modeled by a force field that has been specifically developed and validated for that particular material system (e.g., protein in aqueous solution vs. a crystalline polymer). The interface between the two phases, however, must be separately tuned and validated. To accomplish this, experimental adsorption studies using surface plasmon resonance spectroscopy will be conducted using a designed host-guest peptide system to generate experimental adsorption data that will be used to evaluate, tune, and validate a CHARMM interfacial force field for the accurate simulation of protein adsorption behavior at the solid-solution interface. Once validated, the hybrid force field system will be applied to simulate the adsorption behavior for a biomedically relevant protein on functionalized surfaces and the results will be quantitatively compared with a matched set of experimental studies to demonstrate the developed capabilities to accurately simulate protein adsorption behavior. The successful development of these simulation capabilities will provide the foundations for the establishment of molecular simulation as a valuable tool for the biomaterials community for surface design to study and control protein adsorption behavior at the molecular level, with direct applications for medical device design to enhance implant biocompatibility for improved patient care.