忆起过往事，满是辛酸泪——JACS接收前的心路历程 作者：高辉 写在前面的话： 文章刚刚被化学领域最重要最有影响力的期刊JACS（Journal of the American Chemical Society，美国化学会志）接收，欣慰之余，将其中的心路历程撰写如下，以此作为开通科学网博客暨正式融入科学大家庭的卷首语，但有一二对同行们有益者，也不枉此辛！当然我没有忘记，我仍然是个小菜鸟，仍然需要向同行们学习，欢迎朋友们跟我交流，让我们共同进步吧！ 多少次夜静人稀的校道上踽踽而行？ 多少次睡眼惺忪挣扎着爬出被窝去打开实验室的门？ 多少次心浮气躁坐立不安欲哭无泪？ 多少次不堪重负恍若绝境看不到一丁点光明？ 多少次沉默了亲人的问候？多少次怠慢了朋友的通信？多少次推延了同学的邀请？ 多少次春节没有回家度过？多少次聚会或者活动没有积极参加？ 多少次身边的良辰美景错失？多少次重要的机会没有好好把握？ 多少次在图书馆的书架前被震撼？多少次精彩的演讲没有去听？ 多少次满怀期待终成幻梦？ 多少次郑重承诺化为泡影？ …… 日复一日，年复一年，岁月到底不饶人，如今将要步入而立之年却怎么都立不起来？充斥着无奈压抑着倔强依然孑然一身，功不成名不就老大不小了还要家人操心，年少轻狂的所谓抱负早已消失了影踪，接受着共和国的洗礼却咒骂着现实的不平，爱国兄弟的谆谆教诲却怎么也起不了作用，一边穷困，一边愤青…… 终于，否极泰来不再是梦， JACS 的认可使我此刻成为最幸运的人。 那是二零零六年的秋冬，那时林志强老师的专英要求用英语讲自己的化学研究 presentation ，那时我在学术上一无所有，除了满腔的热情，那时柯卓锋师兄给了我一篇当年的 JPCB 和一篇 CR ，“就拿去讲这个吧”，都是关于磷酸酯水解的论文。那是二零零七年的开春，方冉师兄的一次文献查新得到一篇尚没有页码的刚刚在 JACS 刊出的金属单锌配合物催化磷酸酯水解机理的研究论文。从此坚定了我摸索深入下去的决心。摸索，不停地摸索，尝试，不停的尝试，无数次的失败，无数次的杂七杂八的事情，却并没有动摇我继续摸索下去的决心。因为越走下去越觉得自己的无知渺小，正所谓学无止境。此后，柯卓锋师兄的出国留洋一年，也正是我杂七杂八甚至驰骋三国游戏的一年，期间算了两个月叶保辉老师的水簇，无果，后叶发了 JACS ，据说当时若能计算出来的话是准备发 Science 的，无奈我当时太水太嫩。期间更是算了半年甚至将近一年的 Sm 卡宾环丙烷化反应，终觉无趣，有数据却未成文，亦属无果。转眼间二零零八年的秋冬到了，我也正式博士了，双锌配合物催化磷酸酯水解机理的最新实验研究正好刚出来，这正是我所期盼的，我也从此前的单锌摸索告一段落，磷酸酯的计算仍然停留在 H F/3-21G 水平。零八年十二月的博士开题报告虽然有了一些初步的思路，也着实有一点点初步结果，但这远远不够，……继续摸索，其中的艰辛又岂是只言片语所能概述？跟我一起上研读博的人好几个都已经早早发了文章，得了奖学金，已无毕业压力，只需做自己喜欢做的事情，而我却还在压力之下艰难前行，在零九年七月柯师兄去日本前完成初稿，到一零年七月份投稿到JACS，整整修改了一年，这一年过得太过漫长太过辛劳。没办法，这是我写的第一篇文章，而且又是要投JACS的，在与柯师兄和Nathan几次邮件后，硬是憋啊憋，改啊改，总算最终完稿。 下面是JACS审稿修改全记录： 2010.7.29 投稿到JACS 2010.8.19 第一次修改意见返回，四个审稿人，其中前两个审稿人建议小修改发表，后两个大修改后再审 2010.10.17第一次修改稿发出去（没办法，根据审稿人的意见又算了将近两个月） 2010.11.7第二次修改意见返回，第四审稿人完全同意，第三审稿人却认为我们的回复没有重视他的意见 2010.12.12第二次修改稿发出（又算了一个月，教训啊：审稿人的意见再怎么重视都不过分，谨记啊） 2011.1.6 第三次修改意见返回，（在经历了一个漫长的焦虑等待后忐忑的心总算有了点慰藉了，全是TOP5） 2011.1.9第三次修改稿发出 2011.1.10JACS接收 回顾整个拉锯战过程，我必须向这四位审稿人致以最崇高的敬意，他们都是这个领域最最顶尖的科学家（其中至少有三位可以确定是我推荐审稿人里的六位牛人中的，推荐审稿人也是一门学问，呵呵，要知道，我极不情愿把这些德高望重的牛人们与国内很多披着学术外衣的商人们放在一起，那样是对这些科学良知的人的亵渎），而我这个小菜鸟，能得到他们的指点，从而使得文章更加Perfect（尽管多算了好几个月，尽管提心吊胆战战兢兢了好几个月）。 以下是JACS的总的评审结论汇总： Reviewer: 1 Significance: High Novelty: Moderate Broad interest: High Scholarly presentation: High Are the conclusions adequately supported by the data?: Yes Are the literature references appropriate and correct?: Yes Do the contents justify the length of this manuscript?: Yes Reviewer: 2 Significance: High Novelty: High Broad interest: High Scholarly presentation: High Are the conclusions adequately supported by the data?: Yes Are the literature references appropriate and correct?: In Part Do the contents justify the length of this manuscript?: Yes Reviewer: 3 （第三次评审结论） Significance: Top 5 Novelty: Highest (top 5) Broad interest: Highest (top 5) Scholarly presentation: Highest (top 5) Are the conclusions adequately supported by the data?: Yes Are the literature references appropriate and correct?: Yes Do the contents justify the length of this manuscript?: Yes Reviewer: 4 （第二次评审结论） Significance: High Novelty: High Broad interest: High Scholarly presentation: High Are the conclusions adequately supported by the data?: Yes Are the literature references appropriate and correct?: Yes Do the contents justify the length of this manuscript?: Yes 以下是JACS的总的评审意见汇总： 审稿人一： This paper reports the results of a density functional computational study of the mechanism of phosphate diester cleavage catalyzed by a dinuclear Zn(II) complex. These calculations use a polarizable continuum model to estimate solvation energies for the charged catalyst and reactants. I am not qualified to comment on the quality of the calculations. However, the computational modeling of this metal-ion complex catalyzed reaction presents a very difficult challenge, and I suspect that the author's apparent success is a significant achievement. In addition, the authors have an excellent understanding of earlier experimental studies on these metal ion complexcatalyzed reactions. The agreement between the calculated and observed barrier for the catalyzed cleavage of 2-hydroxypropyl-4-nitrophenyl phosphate is evidence that these calculations provide a true structure for the reaction transition state. In addition, the computational results provide an interesting structure for the Michaelis complex and insight into the reaction mechanism not obtained in experimental studies. This work will attract the attention of computational, organic and inorganic chemists interested in reaction mechanisms. Publication in JACS is recommended, subject to the author's considerations of the following comments and questions. 审稿人二： This manuscript reports a DFT computational study of the hydrolysis of the phosphodiester HpPNP by a binuclear zinc catalyst for which a series of physical organic experimental studies provided data suggestive of a concerted mechanism. The authors’ calculations support that conclusion, as well as the proposals regarding the protonation state of the active species. The abundance of experimental data make this a good system for a computational analysis, and the calculations reproduce the experimental results reasonably well. New insight comes from the nucleophile 18O KIE, which supports the idea that HpPNP binds to the catalyst with the nucleophile hydroxyl group coordinated to one of the zinc ions, and is subsequently deprotonated. This study thus gives a more concrete picture of the binding mode of the substrate to the catalyst than could be determined from experimental results. The binding mode of substrates to dinuclear metallophosphatases, and even to their small molecule model systems, remains an area of considerable uncertainty. Publication is recommended after minor revisions are made. 审稿人三： 第一次审稿意见： In this MS the authors describe a DFT study on the cleavage of 2-hydroxypropyl pnitrophenyl phosphate ( HpPNP ) promoted by a dinuclear Zn(II) catalyst which was experimentally studied extensively by Richard and Morrow. The main findings of this computational study are that the lowest energy computed pathway for cleavage of HpPNP involves double activation of the phosphate by binding to the complex in a Zn(II)—O-P-O—Zn(II) motif, followed by an equilibrium deprotonation of the hydroxypropyl group to form a Zn(II) associated 2-oxypropyl nucleophile which then nucleophilically attacks the phosphoryl unit in a concerted displacement of the pnitrophenoxy group. This pathway fits the mechanism favoured by Richard and Morrow, and supports additional heavy atom kinetic isotope effect studies by Hengge and Richard and Morrow. In addition the authors have computed a less favoured pathway for a stepwise reaction whereby additional waters coordinated to the catalyst displace the phosphate binding from two Zn(II) ions to one Zn(II) ion, with a H-bonding network to the other. This pathway has a general catalysis for the proton transfer with concurrent attack of the 2-oxypropyl group on the P to form a 5-coordinate phosphorane intermediate with subsequent fast departure of the phenoxide leaving group. Overall this is has the makings of a good paper where the computational results on a fairly well-defined system fit with what is known experimentally, and the computation does add to what we know about that system. I have some points that would make the MS clearer and more precise with the presentation. 第二次评审意见： 跟 Fan and Gao 的那篇物理化学的报道的路径的比较 减少 NBO 分析的权重 第三次审稿意见 This is a vastly improved presentation of what is certainly an important contribution to the literature pertaining to a two metal ion catalyzed cleavage reactions of phosphodiesters as models for metallonuclease catalyzed processes. I read this version with interest, in particular the nice presentation of the effects of the various additional calculation parameterization which clearly lead to important energy differences between the methods. I am now happy with the conclusions made, and in particular a more careful comparison of the general-base process of Fan and Gao with the concerted process here, when calculated by methods with the same parameterization. The ms can be published essentially as is, but the authors might like to consider the following three points. 审稿人四： 第一次评审意见： The authors use DFT calculations to investigate the mechanism for the cleavage of an RNA analogue HpPNP catalyzed by a dinuclear Zn(II) complex Zn2(L2O) . The authors identify a plausible cleavage mechanism, which is a fairly routine task with quantum chemical methods. Meanwhile, the authors fall short when characterizing the role of the catalyst, which would have a significant impact in the context of catalyst design. As such, the study is not suitable for publication in JACS in its present form, but may be suitable for other ACS journals. That being said, if a more thorough analysis of the role of the catalyst was performed, and the manuscript was modified accordingly, the study may become suitable for publication in JACS. I would encourage the authors to attempt this route, and provide the following comments regarding the analysis of the mechanism and role of the catalyst. 第二次评审意见： The authors have addressed main point of my previous comments regarding the need for a detailed discussion of the role of the catalyst (comment 1 in my previous report) by adding a section devoted to this purpose. As such, I believe the manuscript is now in sufficient form for publication in JACS.
标签: 反应机理
