## Monday, December 16, 2013

### Postdoctoral position in Theoretical Chemistry, University of Aarhus, Denmark

3-year postdoc position is available

Starting date: 1 February 2014 or as soon as possible.
The candidate must have a PhD in theoretical chemistry. In addition, the candidate is required to have a strong background in electronic structure theory, in particular coupled cluster theory and experience with massive parallel computer codes.

The successful candidate will be involved in the development and implementation of the Divide-Expand-Consolidate (DEC) coupled cluster method in collaboration with other members of the qLEAP Center. Focus will be on a massively parallel implementation of energies, molecular gradients and molecular properties for the DEC coupled cluster CCSD and CCSD(T) models and on running these implementations on the most powerful supercomputers.

For further information on the position, please visit the webpage (http://qleap.au.dk/job-openings & http://qleap.au.dk

## Friday, December 13, 2013

### Review of Hybrid RHF/MP2 geometry optimizations with the effective fragment molecular orbital method

The reviews of +Anders Steen Christensen and +Casper Steinmann PLoS ONE paper are in. Some preliminary thoughts:

Question 1. I think the main problem is that we left out a lot of details because they have been discussed extensively in this paper. So we need to refer to this paper more extensively.

Question 5. Reviewer #2:
Point 1. we should clarify
Point 2. don't understand, in what way unclear
Point 3. we should make such a figure.  We shouldn't show individual fragments, but rather which parts are treated with MP2 and which parts are frozen.

------
From: PLOS ONE
Date: Wed, Dec 11, 2013 at 8:17 PM
Subject: PLOS ONE Decision: Revise [PONE-D-13-43802] - [EMID:f0cd9b87a193051a]
To: "Anders S. Christensen" <xxx>

PONE-D-13-43802
Hybrid RHF/MP2 geometry optimizations with the effective fragment molecular orbital method
PLOS ONE

Dear Mr. S. Christensen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit, but is not suitable for publication as it currently stands. Therefore, my decision is "Major Revision."

We invite you to submit a revised version of the manuscript that addresses the points below:

while this manuscript presents a likely technical advance in QM/MM that could be significant, there is a lack of clarity and context in the manuscript. Each reviewer has noted different aspects that suggest a difficulty in understanding to what extent this method improves upon existing methods, and to what extent this method can be applied across multiple systems.
I encourage you to address each point made by the reviewers. The points relating to comparing this method to others and to explaining discrepancy are particularly important. This manuscript would also benefit from a reorganization and a more critical comparison to other methods.

We encourage you to submit your revision within forty-five days of the date of this decision. I recognize this might not be possible given the recommendations, so I encourage you to ask for an extension if necessary.

When your files are ready, please submit your revision by logging on to http://pone.edmgr.com/ and following the Submissions Needing Revision link. Do not submit a revised manuscript as a new submission. Before uploading, you should proofread your manuscript very closely for mistakes and grammatical errors. Should your manuscript be accepted for publication, you may not have another chance to make corrections as we do not offer pre-publication proofs.

Please also include a rebuttal letter that responds to each point brought up by the academic editor and reviewer(s). This letter should be uploaded as a Response to Reviewers file.

In addition, please provide a marked-up copy of the changes made from the previous article file as a Manuscript with Tracked Changes file. This can be done using 'track changes' in programs such as MS Word and/or highlighting any changes in the new document.

If you choose not to submit a revision, please notify us.

Yours sincerely,

xxx
PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewer's Responses to Questions

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

Reviewer #3: Yes

Reviewer #1: This is relevant paper on using MP2 with effective fragment molecular orbital method and demonstrated to be alternative to ONIOM. The paper would be potentially valuable but I would suggest more discussion about the potential of the method and its outputs to be done. Chorismate mutase is the "hydrogen atom" for QM/MM modelling so there is vast majority of data from many groups, therefore there is a potential in this paper for more comprehensive discussion.

Reviewer #2: (No Response)

Reviewer #3: This study compared the EFMO method with ONIOM method as for the reaction free energy barrier for the Chorismate Mutase. In general, the results are more consistent than that of the ONIOM. This review agrees that the current manuscript is publishable, and expect the authors to explain the possible reasons for: (1) the calculated free energy barrier is much higher than that of the experimentally measured enthalpy change? (2) The authors claimed that the MP2-geometry optimization make it 3.5 kcal/mol lower for the free energy barrier than that of the ONIOM method, however, the listed data of free energy barrier in Table2 is close to each other at the same calculation level. (3) The portability to other enzyme system of EFMO method?

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: N/A

Reviewer #2: I don't know

Reviewer #3: Yes

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: The data of all tables and figures are clean and good.

3. Does the manuscript adhere to standards in this field for data availability?

Authors must follow field-specific standards for data deposition in publicly available resources and should include accession numbers in the manuscript when relevant. The manuscript should explain what steps have been taken to make data available, particularly in cases where the data cannot be publicly deposited.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: This is a typical study on the topic of QM/MM method and application for enzyme reaction.

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors below.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

Reviewer #1: (No Response)

Reviewer #2: The reference should be gived as [1-13]in the text,but not [1,2,3,4,5,6,7,8,9,10,11,12,13].

Reviewer #3: Yes, the whole manuscript is organized very well, and written well.

Reviewer #1: (No Response)

Reviewer #2: The authors implemented the correlated method in the EFMO/FDD approximation on the optimizing a complex of chorismate mutase and chorismate. The authors have presented the transition state structure, reaction barrier, and reaction energy, etc. While the method has more improved the results than the previous work, the paper as present is organized unclearly. There is hardly any insight that can be gained from this word. The manuscript is unsuitable for publication in current version.
To name a few questions.
1. In the theory part, the given molecular system is described, which is defined into tow domains F and A. But in the following description, the b domain (buffer domain) is contained. The system is divided into three domains or two domains?
2. The Table 1 and 2 is disordered.
3. The complex which divided into different domains should show in a figure, which describes the structure and thedevision of different domains in the complex of chorismate mutase and chorismate. It makes the computed model direct and clear.

6. If you would like your identity to be revealed to the authors, please include your name here (optional).

Your name and review will not be published with the manuscript.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

Reviewer #3: (No Response)

## Tuesday, December 10, 2013

### U Copenhagen PhD course: Biostructures and Molecular Modelling in Drug Research

Learning objectives
The course objectives are to introduce participants to different experimental methods and methods in molecular modelling (or computational chemistry) for determination and analysis of three-dimensional structures of biologically important molecules. The application of these methods in the study on relationships between molecular structure and biological activity are dealt with in detail. The course will provide the participants with the opportunity to apply molecular modelling methods to their own research problems.

Content
Nearly all drugs exert their effect by an interaction with a biological macromolecule, i.e. by activation of a receptor or by inhibition of an enzyme. This interaction involves a specific molecular interaction between the drug (the ligand) and the macromolecule (often a protein). Today, considerable information has been accumulated about the relationships between structure and activity for most types of drugs. Nevertheless, knowledge about the molecular interactions between the drug molecule and the macromolecule in the organism is still limited in most cases.
The most important experimental method for determination of structures of organic molecules is X-ray crystallography. By X-ray crystallographic methods it is possible to determine high-resolution three-dimensional structures of small molecules as well as macromolecules such as proteins. NMR spectroscopy and molecular modelling methods represent alternative methods for the determination of three-dimensional structures and biologically relevant targets.
The term, molecular modelling, comprises a variety of computer-based methods used to construct three-dimensional models of chemical compounds, and to calculate a number of different characteristics for the compounds (e.g. shape, flexibility, charge distribution, lipophilicity). Computer graphics is very important for visualisation of the molecules and their characteristics.
Molecular modelling makes it possible to construct models of already known molecules, but also unknown or not yet synthesised molecules can be investigated. With molecular modelling it is possible to study the relationships between molecular structure and various properties, and to assist in design of compounds with preselected properties.

Molecular modelling and computer graphics are powerful tools in the study of the relationships between molecular structure and biological activity, and thus essential in the process of rational drug design. Molecular modelling has become an indispensable part of modern medicinal chemistry and during the last decade the methods have been implemented in most pharmaceutical companies.

During the course a number of examples of biological (pharmaceutical) importance will be presented and discussed with special emphasis on the following topics:
- Molecular structures and 3D-databases: Experimental methods (X-ray crystallography and NMR spectroscopy), computational methods (homology building) and 3D-databases including crystallographic databases (Protein Data Bank),.
- Molecular mechanics-based methods: Different force fields (potential functions, parameters, limitations), energy minimisation, charges, electrostatics and molecular dynamics simulations.
- Quantum mechanics methods: Approximations, basis set, determination of properties (e.g. structures, energies, charges).
- Structure-activity analyses: Conformational analysis, conformational energies, conformational search methods, template fitting and pharmacophore identification.
- Protein-ligand interactions: Binding energies, docking, structure-based molecular design, de novo design.
- ADME (absorption, distribution, metabolism and excretion) modelling.

The practical exercises will include tutorials aimed at learning specific tasks and projects based on the participants' own research activities.

## Monday, December 2, 2013

### Notes on fugacity and activity

This is one of those "note to self" posts where I try to get my head around a concept, this time fugacity and activity for a gas.

$dG=Vdp-SdT \implies dG=Vdp \text{ if } dT=0$
$$G(p)=G^\circ+\int_{p^\circ}^{p}Vdp$$
If the gas is ideal, i.e. for one mole $V=RT/p$, then
$$G(p)=G^\circ+RT\int_{p^\circ}^{p}\frac{dp}{p}=G^\circ+RT\ln\frac{p}{p^\circ}$$
For $A\rightleftharpoons B$
$$G(p_B)-G(p_A)=0 \implies \frac{p_B}{p_A}=e^{-\Delta G^\circ/RT}$$
What about a real gas where $V\neq RT/p$?  We introduce the fugacity $(f)$ for which $V=RT/f$ so that
$$G(p)=G^\circ+RT\ln\frac{f}{p^\circ} \text{ and } \frac{f_B}{f_A}=e^{-\Delta G^\circ/RT}$$
To determine $f$:
$$\int_{p'}^{p} (V-V_{ideal})dp=RT\ln\left(\frac{f}{f'}\cdot \frac{p'}{p}\right) = RT\ln\left(\frac{f}{p}\cdot \frac{p'}{f'}\right)$$
Gases approach ideality at low pressure: $f'/p'\rightarrow 1$ as $p\rightarrow 0$ so:
$$\ln\left(\frac{f}{p}\right)=\ln(\phi)=\frac{1}{RT}\int_{0}^{p} (V-V_{ideal})dp$$
So for sticky non-ideal gases for which $V<V_{ideal}$ the fugacity coefficient $\phi$ is less than 1.  So even though $V=RT/f$ don't confuse $f$ with $p_{ideal}: f<p<p_{ideal}$ for a given number of gas particles.

Finally the relationship between fugacity and activity ($a$) is
$$a=\frac{f}{p^\circ}$$.