Force Field Development for Protein Absorption Modeling

描述(申请人提供)：由于其在种植体生物相容性中的主导作用，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。虽然非常需要，但对蛋白质吸附是如何发生的，以及如何控制它，仍然缺乏详细的分子水平的了解。分子模拟提供了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，必须专门为这一应用开发方法。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，以使两种不同的力场(I类或II类)能够在同一模拟中使用，以分别表示溶液相和固相。这将使吸附体系的两个相都可以通过为特定材料体系(例如，水溶液中的蛋白质与结晶聚合物)专门开发和验证的力场来准确建模。然而，两个阶段之间的接口必须单独调整和验证。为此，将使用设计的主客体多肽系统进行使用表面等离子体共振光谱的实验吸附研究，以生成实验吸附数据，该数据将用于评估、调整和验证CHARMM界面力场，以准确模拟蛋白质在固-溶液界面的吸附行为。一旦得到验证，混合力场系统将被应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，结果将与一组匹配的实验研究进行定量比较，以展示所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，分子模拟将成为生物材料表面设计的宝贵工具，在分子水平上研究和控制蛋白质的吸附行为，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.