From owner-chemistry@ccl.net Fri Apr 5 11:08:00 2019 From: "Norrby, Per-Ola Per-Ola.Norrby|,|astrazeneca.com" To: CCL Subject: CCL: Catalyzed reactions Message-Id: <-53669-190405004641-2037-78Oaq1Brrno49z4xyhxwuA%x%server.ccl.net> X-Original-From: "Norrby, Per-Ola" Content-Language: en-US Content-Transfer-Encoding: 8bit Content-Type: text/plain; charset="us-ascii" Date: Fri, 5 Apr 2019 04:46:28 +0000 MIME-Version: 1.0 Sent to CCL by: "Norrby, Per-Ola" [Per-Ola.Norrby|astrazeneca.com] Dear Benoit, The most common path for a catalytic reaction is that the catalyst picks up one reagent at a time, forming a succession of intermediates, until finally the product(s) get eliminated from the complex and the catalyst is regenerated. Finding out the order in which the reagents get attached, and any bond rearrangements that happen in these complexes, is what a mechanistic study is about. You'll simply have to go through all possibilities and determine which of many plausible paths has the lowest overall barrier. You should also realize that our computational tools are not perfect, there can be errors in the calculated energies, so it's very good to check that the path you end up with really fits the available experimental data, such as reaction orders. You find the highest energy point on your preferred path, that is the rate limiting transition state. Then you go backwards to the lowest energy preceding point, including any side paths that could point to inhibition of the catalyst complex. That lowest point is the resting state, and should be observable. Now, the entire sequence from the resting state until the rate limiting transition state is your rate limiting step (which can be composed of many elementary steps). Any components that get added when going from the resting state to the rate limiting TS will have a positive reaction order. If something has to be lost (for example, if something can bind to the catalyst and inhibit it) it will have a negative reaction order. If not all predicted reaction orders are observed, then there is some error in your path; your level of theory may not be sufficient, or you forgot accounting for some critical component. Note that your calculations assume that all components are at the standard state, 1 M in solution. Real concentrations deviate from that, so you'll have to apply standard state corrections. For example, if some component can bind to the catalyst and inhibit it, but the component has a very low concentration, the real energy of that complex may increase and may no longer be the resting state after the standard state correction. For this reason, the corrected free energy surface can change during the course of the reaction. Best regards, Per-Ola Norrby -----Original Message----- > From: owner-chemistry+per-ola.norrby==astrazeneca.com|*|ccl.net On Behalf Of Benoit Gearald ablux13*gmail.com Sent: den 4 april 2019 21:50 To: Norrby, Per-Ola Subject: CCL: Catalyzed reactions Sent to CCL by: "Benoit Gearald" [ablux13|gmail.com] Dear CCLers, When a reaction between two reactants happens in the presence of a given catalyst, I am enquiring about where to put the catalyst in other words on which reactant to theoretically find the pathway? Any help is appreciated Benoithttps://clicktime.symantec.com/36ai1NEfS7ECpKH2oymEV5a6H2?u=http%3A%2F%2Fwww.ccl.net%2Fcgi-bin%2Fccl%2Fsend_ccl_messagehttps://clicktime.symantec.com/36ai1NEfS7ECpKH2oymEV5a6H2?u=http%3A%2F%2Fwww.ccl.net%2Fcgi-bin%2Fccl%2Fsend_ccl_messagehttps://clicktime.symantec.com/3JpF7APDsYysVgswpS82F2r6H2?u=http%3A%2F%2Fwww.ccl.net%2Fchemistry%2Fsub_unsub.shtml Before posting, check wait time at: https://clicktime.symantec.com/3x5qaVXHcGTeDr4CHUBBoY6H2?u=http%3A%2F%2Fwww.ccl.net Job: https://clicktime.symantec.com/3G8sv5LaMt7q3U66UkSzrmU6H2?u=http%3A%2F%2Fwww.ccl.net%2Fjobs Conferences: https://clicktime.symantec.com/33Focg5FCDYKSJa3A19aNYA6H2?u=http%3A%2F%2Fserver.ccl.net%2Fchemistry%2Fannouncements%2Fconferences%2F Search Messages: https://clicktime.symantec.com/32ff92ztQaKb7ymVEzjYTkz6H2?u=http%3A%2F%2Fwww.ccl.net%2Fchemistry%2Fsearchccl%2Findex.shtmlhttps://clicktime.symantec.com/3RRStnjta9sH5gFhXbChxyq6H2?u=http%3A%2F%2Fwww.ccl.net%2Fspammers.txt RTFI: https://clicktime.symantec.com/3HnwjWQ9LzZ4mU4FBUD9yqZ6H2?u=http%3A%2F%2Fwww.ccl.net%2Fchemistry%2Faboutccl%2Finstructions%2F ________________________________ Confidentiality Notice: This message is private and may contain confidential and proprietary information. If you have received this message in error, please notify us and remove it from your system and note that you must not copy, distribute or take any action in reliance on it. Any unauthorized use or disclosure of the contents of this message is not permitted and may be unlawful. From owner-chemistry@ccl.net Fri Apr 5 22:09:00 2019 From: "Sebastian Kozuch seb.kozuch[#]gmail.com" To: CCL Subject: CCL: Catalyzed reactions Message-Id: <-53670-190405140634-6222-K7THnLoMfsHqK5JJ+0WS4g===server.ccl.net> X-Original-From: Sebastian Kozuch Content-Language: en-US Content-Transfer-Encoding: 7bit Content-Type: text/html; charset=utf-8 Date: Fri, 5 Apr 2019 21:06:25 +0300 MIME-Version: 1.0 Sent to CCL by: Sebastian Kozuch [seb.kozuch]~[gmail.com] Slightly off topic, but I would like to give an opinion on something we discussed with Per-Ola years ago. Although his summary is very good, I would like to say that the use of a "rate determining step" as the whole section between the resting state and the rate determining transition state is, to me, quite misleading. For me, a step is an elementary step (i.e. two intermediates connected by a single transition state, basically a concerted reaction). Maximum, I can agree that some conformational changes can be included into the step, as they are almost irrelevant to the kinetics (although very relevant when computing the complete reaction).
But consider the case where the resting state is right at the beginning of the reaction, and the determining transition state is right at the end. According to the previous definition, the "step" would be the complete multi-step reaction! Clearly we need a different word for the zone between the resting state and the determining TS. Luckily it exists, and it is called the "rate determining zone" (Yagisawa, "Enzyme Kinetics Based on Free-Energy Profiles." Biochem. J. 1995, 308, 305).
I would like to emphasize what Per-Ola said: Any reactant that enters into the cycle in the determining zone will have order one (minus one for products), while any species entering the cycle outside the zone will have order zero. This is an extremely powerful concept in kinetics that almost never appear in textbooks.

Best,
Sebastian Kozuch



On 5/4/19 7:46 AM, Norrby, Per-Ola Per-Ola.Norrby|,|astrazeneca.com wrote:
Sent to CCL by: "Norrby, Per-Ola" [Per-Ola.Norrby|astrazeneca.com]
Dear Benoit,

The most common path for a catalytic reaction is that the catalyst picks up one reagent at a time, forming a succession of intermediates, until finally the product(s) get eliminated from the complex and the catalyst is regenerated. Finding out the order in which the reagents get attached, and any bond rearrangements that happen in these complexes, is what a mechanistic study is about. You'll simply have to go through all possibilities and determine which of many plausible paths has the lowest overall barrier.

You should also realize that our computational tools are not perfect, there can be errors in the calculated energies, so it's very good to check that the path you end up with really fits the available experimental data, such as reaction orders. You find the highest energy point on your preferred path, that is the rate limiting transition state. Then you go backwards to the lowest energy preceding point, including any side paths that could point to inhibition of the catalyst complex. That lowest point is the resting state, and should be observable. Now, the entire sequence from the resting state until the rate limiting transition state is your rate limiting step (which can be composed of many elementary steps). Any components that get added when going from the resting state to the rate limiting TS will have a positive reaction order. If something has to be lost (for example, if something can bind to the catalyst and inhibit it) it will have a negative reaction order. If not a!
 ll predicted reaction orders are observed, then there is some error in your path; your level of theory may not be sufficient, or you forgot accounting for some critical component.

Note that your calculations assume that all components are at the standard state, 1 M in solution. Real concentrations deviate from that, so you'll have to apply standard state corrections. For example, if some component can bind to the catalyst and inhibit it, but the component has a very low concentration, the real energy of that complex may increase and may no longer be the resting state after the standard state correction. For this reason, the corrected free energy surface can change during the course of the reaction.

Best regards,

Per-Ola Norrby

-----Original Message-----

From: owner-chemistry+per-ola.norrby==astrazeneca.com%%ccl.net <owner-chemistry+per-ola.norrby==astrazeneca.com%%ccl.net> On Behalf Of Benoit Gearald ablux13*gmail.com

Sent: den 4 april 2019 21:50
To: Norrby, Per-Ola <Per-Ola.Norrby%%astrazeneca.com>
Subject: CCL: Catalyzed reactions


Sent to CCL by: "Benoit  Gearald" [ablux13|gmail.com] Dear CCLers,

When a reaction between two reactants happens in the presence of a given catalyst, I am enquiring about where to put the catalyst in other words on which reactant to theoretically find the pathway?

Any help is appreciated

Benoithttps://clicktime.symantec.com/36ai1NEfS7ECpKH2oymEV5a6H2?u=http%3A%2F%2Fwww.ccl.net%2Fcgi-bin%2Fccl%2Fsend_ccl_messagehttps://clicktime.symantec.com/36ai1NEfS7ECpKH2oymEV5a6H2?u=http%3A%2F%2Fwww.ccl.net%2Fcgi-bin%2Fccl%2Fsend_ccl_messagehttps://clicktime.symantec.com/3JpF7APDsYysVgswpS82F2r6H2?u=http%3A%2F%2Fwww.ccl.net%2Fchemistry%2Fsub_unsub.shtml

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