Methods for Calculating the Free Energy of Proteins

描述（由申请人提供）：我们建议开发计算生物大分子系统绝对熵S和自由能F的有效方法，这是计算机模拟中极其困难的问题。S是有序的度量，它定义；例如，蛋白质表面环的柔韧性，构成了蛋白质折叠的重要驱动力。F（而不是能量E）是正确的稳定性标准，用于预测蛋白质的天然结构；在合理的药物设计过程中，如配体与酶活性位点的灵活对接、蛋白质-蛋白质识别过程和酶促反应中，它是必不可少的。计算s -ln P需要知道采样概率F的值，这不是由蒙特卡罗或分子动力学模拟直接提供的；因此F=E-TS也是未知的。常用的方法是基于热力学积分，其中得到状态m和n之间的自由能，delta，n的差值。对于结构方差较大的m和n，由于需要沿积分路径进行大量的模拟，这些方法变得不切实际。然而，如果In P是已知的，则绝对Fm和Fn，因此deltaFm，n = Fm - Fn，只能从两个单独的模拟中得到，即使对于非常不同的状态。PT提出了计算S和F的两种近似方法，即局部状态法（LS）和假设扫描法（HS），并发现它们对大量系统非常有效。对于经历局部波动的系统（例如，围绕a-螺旋），LS的效率明显高于HS，而HS对随机线圈聚合物的效率最高。这个项目的一个目标是设计出LS和HS的混合方法，并且可以优化任何链的灵活性。该混合方法特别适用于由力场和隐式溶剂化建模的蛋白质，将测试其在线性和环状肽以及蛋白质表面环中的应用。LS也将逐步扩展，首先是液态氩，然后是液态水的TIP4P模型，最后是浸泡在显水“盒子”中的肽，其中将计算α -螺旋和发夹状态的相对稳定性。因此，分子建模和药物设计所需的有效工具将成为可能。在未来，这些方法将被PI纳入处理灵活性的新方法中，现在应用于生物感兴趣的表面回路；它们还将用于灵活对接的新程序。

DESCRIPTION (provided by applicant): We propose to develop efficient methods for calculating the absolute entropy S and the free energy F for biomacromolecular systems an extremely difficult problem in computer simulation. S is a measure of order, which defines; for example, the extent of flexibility of surface loops in proteins, and constitutes an essential driving force in protein folding. F (rather than the energy E) is the correct criterion of stability, required to predict the protein's native structure; it is indispensable in procedures for rational drug design such as flexible docking of ligands to active sites of enzymes, protein-protein recognition processes, and enzymatic reactions. Calculating s -ln P requires knowing the value of the sampling probability F, which is not provided directly by Monte Carlo or molecular dynamics simulations; therefore, F=E-TS is also unknown. The commonly used methods are based on thermodynamic integration where the difference in free energy, deltafm,n between states m and n is obtained. For m and n with large structural variance these methods become impractical because of the large number of simulations required along the integration path. However, if In P is known, the absolute Fm and Fn, hence deltaFm,n = Fm - Fn, can be obtained from two separate simulations only even for very different states. Two approximate methods for calculating S and F, the local states (LS) and the hypothetical scanning (HS) methods, were developed by the PT and were found to be extremely efficient for a large number of systems. LS is significantly more efficient than HS for systems undergoing local fluctuations (e.g., around an a-helix), while HS is most efficient for random coil polymers. One objective of this project is to devise methods that are hybrids of LS and HS and can optimally be tuned for any chain flexibility. The hybrid methods, which are especially suited for a protein modeled by a force field and implicit solvation, will be tested as applied to linear and cyclic peptides and surface loops in proteins. LS will also be extended gradually first to liquid argon, then to the TIP4P model of liquid water, and finally to a peptide soaked in a "box" of explicit water, where the relative stability of alpha-helical and hairpin states will be calculated. Thus, much needed efficient tools for molecular modeling and drug design will become available. In the future, these methods will be incorporated by the PI within a new methodology for treating flexibility, applied now to surface loops of biological interest; they will also be used in new procedures for flexible docking.