COMPUTATIONAL ANALYSIS OF PEPTIDE/LIPID INTERACTIONS AND AT MEMBRANE SURFACES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 保留字： 有限差分Poisson-Boltzmann，蛋白质/脂质相互作用，亚细胞靶向，静电，膜 摘要： 这是一份申请，要求延长我们从2004年1月10日开始获得的NSF高性能计算和TeraGrid站点分配委员会的资助，编号为MCB 030028（也被列为PSC资助MCB 020050 P），期限为2004年1月10日至2005年9月30日，该资助可能持续三年。虽然这一时期是一个非常富有成效的时期，但我们已经严重透支了这笔赠款。作为这个项目的PI，我对此承担全部责任，只能提供以下解释：1）该资源非常适合我们的计算需求，以至于学生和博士后将其用于原始提案中未包含的其他项目，2）去年我病得很重（包括一次大手术和两次住院），并没有充分地让我实验室的用户记住负责任使用的方案。我对这种情况深表歉意，特别是后者，我希望这份报告，其中简要介绍了我们增加的使用和新的严格的使用协议，将有助于说服拨款委员会原谅透支，并允许我们在这一期间延长我们目前的拨款。具体来说，我们谦卑地要求在PSC HP Marvel上增加20，000 SU，超过迄今为止已经使用的约100，000 SU，并且我们仍然可以保留对我们的TeraGrid宽漫游SU的访问。我们将非常感谢第二次机会，并希望我们可以获得继续访问惠普奇迹通过09/30/04。我同时提交了一份进度报告，其中提供了有关我们当前项目的更多详细信息，这些项目得到了我们NSF高性能计算奖的支持。本报告还描述了我们在此期间的生产力。我们一直在使用TeraGrid PSC HP Marvel，在建模具有重要生物相关性的多组分大分子复合物方面取得了巨大成功。因此，这种资源对我们的研究计划的成功至关重要。正如我们最初的提议中所描述的，拟议研究的长期目标是表征外周膜蛋白与磷脂膜结合的结构和能量基础，进而更好地理解细胞中膜介导事件的生物物理基础。有限差分Poisson-Boltzmann（FDPB）方法已被证明是非常准确的，它的能力，以占许多实验确定的蛋白质/膜系统的静电特性，我们正在应用这种连续方法沿着的半经验方法来表征疏水性的贡献膜协会以下问题。我们最初的建议的具体目标是寻求一个精心挑选的外周膜蛋白家族的集合的膜结合行为的特征。虽然每个家族都有独特的膜结合行为，但它们的膜结合最终可以通过静电和疏水相互作用的相互作用来描述。在过去的一年中，我们已经建立在以前的方法，更准确地描绘蛋白质/膜系统的物理特性，我们已经扩大了我们的重点，包括其他蛋白质家族与自己的有趣的膜结合特性。（与我们最初的目标和拟议的新项目有关的进展载于我们的进展报告。细胞生物学中的一个基本问题是如何实现和调节蛋白质向不同细胞膜的募集。我们实验室的主要研究目标是使用计算方法来了解细胞信号传导过程和病毒组装中膜靶向的物理，分子和结构基础。详细解剖的分子机制的膜结合行为的范围广泛的外周蛋白将有助于理解亚细胞靶向以及合理设计的药物，抑制膜结合的生物过程中，导致疾病状态。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Keywords: Finite difference Poisson-Boltzmann, protein/lipid interactions, subcellular targeting, electrostatics, membranes Abstract: This is a request for an extension of the grant we were awarded beginning 10/01/04 by the NSF High-performance Computing and TeraGrid Sites Allocations Committee, number MCB030028 (also listed as PSC grant MCB020050P) for the period 10/01/04-09/30/05, with the possibility of the award continuing for three years. While this period has been an extremely productive one, we have significantly overdrafted this grant. As PI for this project, I take full responsibility for this and can only offer the explanations that 1) the resource was so well-suited to our computational needs that students and postdocs used it for additional projects not included in the original proposal, and 2) I was very ill this past year (including a major surgery and two hospital stays) and did not adequately impress upon the users in my lab the protocol for responsible usage. I deeply apologize for this situation, especially the latter, and it is my hope that this report, which briefly describes our increased usage and a new stringent usage protocol, will help convince the Allocations Committee to forgive the overdraft and grant us an extension of our current allocation for this period. Specifically, we are humbly asking for an additional 20,000 SU on the PSC HP Marvel above and beyond the ~ 100,000 SU already used to date and that we may still retain access to our TeraGrid Wide Roaming SUs. We would greatly appreciate a second chance and hope that we may be granted continued access to the HP Marvel through 09/30/04. I have simultaneously submitted a Progress Report which provides more detail on our current projects which are being supported by our NSF High-performance Computing award. This report also describes our productivity during this period. We have been using the TeraGrid PSC HP Marvel with great success in modeling multi-component macromolecular complexes of significant biological relevance. This resource is, thus, crucial to the success of our research program. As described in our original proposal, the long term objective of the proposed research is to characterize the structural and energetic basis for the binding of peripheral membrane proteins to phospholipid membranes and, in turn, to better understand the biophysical basis of membrane-mediated events in cells. The finite difference Poisson-Boltzmann (FDPB) method has proved extremely accurate in its ability to account for many of the experimentally determined electrostatic properties of protein/membrane systems, and we are applying this continuum method along with a semi-empirical approach to characterize the hydrophobic contribution to membrane association to the following problems. The specific aims of our original proposal seek to characterize the membrane binding behaviors of a collection of carefully selected families of peripheral membrane proteins. While each family has unique membrane binding behaviors, their membrane association can ultimately be described by the interplay of electrostatic and hydrophobic interactions. During the past year we have built on previous methodology to more accurately depict the physical properties of protein/membrane systems, and we have expanded our focus to include other protein families with their own interesting membrane binding characteristics. (Progress related to our original aims and proposed new projects are provided in our Progress Report.) A fundamental question in cell biology is how the recruitment of proteins to different cellular membranes is achieved and regulated. The major research objective in our lab is to use computational approaches to understand the physical, molecular and structural bases of membrane targeting in cellular signaling processes and in viral assembly. A detailed dissection of the molecular mechanisms underlying the membrane binding behaviors of a wide range of peripheral proteins would facilitate the understanding of subcellular targeting as well as the rational design of drugs that inhibit membrane binding in biological processes that lead to disease states.