Computational Chemistry

1. Module where the subject is included. Relation to other subjects.

Module IV: Reactivity and Synthesis. The subject of Computational Chemistry relates to other subjects within its own module (Catalysis, Chemical Synthesis and determination of reaction mechanisms), but also has strong crosscutting with numerous subjects of the degree taught in other modules, mainly with the subjects of Biological and Cellular Chemistry, Supramolecular Chemistry and Biophysics (Module II) and the subjects Nanostructured Materials and Molecular Materials (Module III). The subject is a fundamental complement to the rest of the modules.


2. Role played by this subject in the corresponding module and in the whole of the Curriculum.

The objective of this subject is to understand the basic concepts of computational chemistry. It is intended that the student knows and understands the different methodologies that can be used to solve a problem using computational chemistry. The theoretical bases of these methodologies will be studied, with special emphasis on a considerable number of applications that will allow the student to know the most used programs and methods to perform computational calculations of molecular properties and chemical reactivity, currently essential to contrast and predict results in a rigorous, faster and cheaper way than the experimental method. Given the transversal role of these computational methodologies, the student will be shown an integral and multidisciplinary view of computational chemistry within the area, in the context of other branches of science. Thus, the student will understand the synergy between experimental methods and theoretical and computational chemistry.


3. Prior knowledge (recommended / compulsory) that students must possess to take the course.

Although it is not mandatory, basic knowledge of Linux and / or programming is recommended. However, all the necessary knowledge for the correct comprehension of the contents of the subject will be imparted to the students.

4. Learning objectives

- Understanding the basis of computational chemistry
- Knowing and understanding the different methodologies that can be used to solve a problem using computational chemistry.
- Obtaining a comprehensive and multidisciplinary vision of the area, in the context of other branches of science.
- Understanding the existing synergy between experimental methods and theoretical and computational chemistry.
- Knowing the applications of computational chemistry

1. Course epigraphs:

Lesson 1. Introduction to Computational Chemistry. Quantum methods and classical methods. Basic tools: Linux, Bash, Python and molecular visualizers.
Session 1 (EXP1 + EXP2)

Lesson 2. Quantum mechanics. General concepts and application to the study of reaction mechanisms and the prediction of molecular properties.
Session 2 (EXP3 + P1), Session 3 (EXP4 + P2), Session 4 (EXP5 + P3) and Session 5 (EXP6 + P4)

Lesson 3. Molecular Mechanics and Molecular Dynamics. Theoretical bases and applications in organic chemistry and biological chemistry.
Session 6 (EXP7 + P5) and Session 7 (EXP8 + P6)

Lesson 4. Docking and QM / MM: General concepts. Applications to enzymatic catalysis.
Session 8 (EXP9 + P7) and Session 9 (EXP10 + P8)

2. List of practices of the subject:

Practice 1. Conformational search, minimum and energy surfaces (Session 2 and Session 3)
Practice 2. (Session 4 and Session 5)
Practice 3. Molecular Dynamics of a biological system (Session 6 and Session 7)
Practice 4. Study of the reaction mechanism in the active center of an enzyme (Session 8 and Session 9)

3. List of exercise bulletins of the subject:

Bulletin 1. Introduction to Linux and Bash basic instructions
Bulletin 2. Introduction to programming with Python
Bulletin 3. Introduction to computational simulation: using quantum methods and classical methods for the resolution of problems with biological and supramolecular systems.

Lesson 1. Introduction to Computational Chemistry. Quantum methods and classical methods. Basic tools.

This lesson takes place in a session of 2 hours (Session 1). During the first part of the session (15 minutes) the program content to be developed as well as the teaching and evaluation methodology is described, clarifying any doubts that the students may have about it.
The subject begins with an introduction to Computational Chemistry, with special emphasis on the difference between quantum methods and classical methods. The main advantages and limitations of each of them are explained, making reference to the type of chemical, supramolecular and biological problems that can be addressed with the different computational methodologies that are currently available. It is important that students understand the existing synergy between experimental methods and theoretical and computational chemistry, and obtain a comprehensive and multidisciplinary view of the area, in the context of other branches of science. The historical background of both methods is reviewed, their evolution over time and their future perspectives, relating them to the parallel development of the supercomputing to which they are associated.
Next, the need to possess some basic concepts of some general computational tools, such as the use of the Linux operating system, the Bash and Python languages ​​and the use of visualizers and molecular constructors is exposed. The objective is to give the student a general vision of these basic computational tools, transversal to the different computational methodologies that will be addressed in the subject. For this purpose, in order for the student to acquire skills in the use of these computational tools, all the concepts explained during the lesson are complemented by the resolution of two practical exercises bulletins (Bulletin 1 and Bulletin 2). The students install the XmobaTerm tool (https://mobaxterm.mobatek.net/) or an analogous tool for MAC and they connect to CESGA, where practically all the necessary programs for the resolution of the exercises are already installed. It is convenient that students install a VPN server on their personal computers in order to work outside the classroom in the contents of the subject. Throughout Session 1 the students solve some exercises outlined in the bulletins, with the help of the explanations provided by the teacher. The rest of the exercises of the bulletins are considered as non-classroom work that the student must carry out to improve their skills in the use of these basic computational tools, using the Seminars and Tutorial sessions to resolve any doubts that may arise in their autonomous resolution.

RECOMMENDED LITERATURE:
Material deposited in the virtual classroom.
Introduction to Computational Chemistry:
-Molecular Modeling. Principles and Applications (Ed Pearson Education, 2001), Andrew R. Leach
-Introduction to Computational Chemistry (Ed Wiley), Frank Jensen.
Introduction to Linux and Bash:
-https://computernewage.com/2018/09/16/scripting-linux-introduction/
-https://www.howtoforge.com/tutorial/linux-shell-scripting-lessons/
-https : //linuxconfig.org/bash-scripting-tutorial-for-beginners
Introduction to Python:
-https://www.python.org/about/gettingstarted/
-https://www.learnpython.org/en/
Molecular Viewers :
-http://cheminf.cmbi.ru.nl/molden/
-http://www.cambridgesoft.com/support/ProductHomePage.aspx?KBCatID=112
-http://www.ks.uiuc.edu/Training /Tutorials/vmd-index.html
-http://pymol.sourceforge.net/newman/user/toc.html
-https://avogadro.cc/

Lesson 2. Quantum mechanics. General concepts and application to the study of reaction mechanisms and the prediction of molecular properties.

This theme is developed in four sessions, each lasting 2 hours (Session 2-Session 5), constituted by a combination of expository class and practical class. The aim of this methodological scheme is to promote self-learning of the student, relating the assimilation of theoretical concepts to the resolution of problems and practical situations that could be found in their possible professional future.
In this subject the student becomes familiar with the methods of the electronic structure. First, the concept of potential energy surface (SEP) is introduced within the Born-Oppenheimer approach. In this context, it is important to indicate the different functional forms to construct the SEP and that go from the potential of a link voltage to torsion potentials or van der Waals interactions.
Once the SEP concept and how it is constructed has been introduced (at least analytically), it is important that the student knows how to determine the stationary points of a potential energy surface; This naturally leads to the concept of geometric optimization.
Once these concepts are introduced, the methods of the electronic structure are described using different levels of approximation. It begins with semi-empirical methods, continuing with the DFT methods and ending with ab initio methods. The calculations of the electronic structure allow obtaining a large amount of information about the molecular properties of the system under study: dipole moments, electrostatic potential, atomic charges, polarizability and hyperpolarizability, etc. It is also possible to calculate partition functions, which lead directly to the calculation of thermodynamic functions such as enthalpy, entropy and Gibbs free energy.
Both the calculation of partition functions and that of thermodynamic properties can be used to obtain an estimate of the velocity constant of a chemical reaction; in particular they can be used to calculate kinetic constants using the transition state theory. This section also discusses some factors that may influence the kinetics such as non-statistical effects and the tunnel effect.

RECOMMENDED LITERATURE:
Material deposited in the virtual classroom.
-IN Levine, Quantum Chemistry, 5th Ed., Pearson Education (2001).
- CJ Cramer, Essentials of Computational Chemistry, John Wiley & Sons (2002).
- F. Jensen, Introduction to Computational Chemistry, 2nd Edition, John Wiley & Sons (1999).
- PW Atckins, RS Friedman, Molecular Quantum Mechanics, 3rd Ed., Oxford Univ. Press (1997).
- PW Atkins, RS Friedman, Solutions Manua l for Molecular Quantum. Oxford Univ. Press (1997).
- A. Szabo, NS Ostlund, Modern Quantum Chemistry. Introduction to Advanced Electronic Structure Theory, Dover Pub., Inc. (1996).
- T. Helgaker, P. Joergensen, J. Olsen, 'Molecular Electronic-Structure Theory', John Wiley & Sons (2000).
- J. Simons, J. Nichols, Quantum Mechanics in Chemistry, Oxford Univ. Press (1997).
- JB Foresman, Æleen Frisch, Exploring Chemistry with Electronic Structure Methods, 2nd Ed., Gaussian, Inc. (1995-96).

Lesson 3. Molecular Mechanics and Molecular Dynamics. Theoretical bases and applications in organic chemistry and biological chemistry.

This theme is developed in two sessions, each lasting 2 hours, constituted, once again, by a combination of expository class and practical class (Session 6-Session 7).
The aim of these two sessions is to introduce the theoretical basis of classical methods and present the computational methodologies most used today in this field: Molecular Mechanics, Docking, Virtual Screening and Molecular Dynamics. Once these concepts are introduced, the most used software packages corresponding to each of these methodologies are discussed (Chemoffice, Avogadro, Autodock, Gold, Gromacs, Amber, NAMD, etc). Next, the fundamental bases of Molecular Dynamics are described, commenting on the resolution levels most used today in multiscale simulations: atomistic and coarse-grained (CG). The usefulness of these approaches is explained in order to approach larger systems for longer times, something very important and necessary in biological systems. Finally, some applications of this methodology to biological and supramolecular systems are also shown so that the student understands what kind of information can be obtained with this technique. It is important that the student knows the different methodologies and understands that not all of them are adequate to study a certain system or process, as well as that it is sometimes possible to use more than one of them to address the same chemical or biological problem, in a complementary way.
To link with the practical part, the necessary files in a simulation of this type are presented using the free software package GROMACS: mdp, topology, tpr, xtc, gro, pdb, etc. The teacher explains how to carry out the preparation of the necessary files for the program entry, how the generated .tpr is executed, and how a molecular dynamics trajectory is analyzed. Next, the student prepares the input files for GROMACS (.top, .pdb, .mdp) to carry out the simulation of molecular dynamics of a biological system and executes the simulation in the supercomputer center (CESGA). For reasons of time, the professor will make available to the students the output files of the molecular dynamics, making them aware of the execution times that the simulations would imply if they had been executed completely in the supercomputer center. Using these output files, the student carries out the main analysis of the trajectory: visualization of the last output structure, RMSD, hydrogen bonds, etc. The practice also includes an exercise in which the student has to use the concepts learned in Session 1, and develop a small code in Python to analyze a property determined from the trajectory obtained in the simulation and validate it with the analysis of the same property but carried out through the analysis tools integrated in GROMACS.

RECOMMENDED LITERATURE:
Material deposited in the virtual classroom.
-Molecular Modeling. Principles and Applications (Ed Pearson Education, 2001), Andrew R. Leach
-Introduction to Computational Chemistry (Ed Wiley), Frank Jensen.
MOLECULAR DYNAMICS:
http://www.gromacs.org/Documentation/Terminology/Molecular_Dynamics_Sim…
http://www.mdtutorials.com/gmx/
http://www.gromacs.org/Documentation/Tutorials
http://cgmartini.nl /index.php/tutorials

Lesson 4. Docking and QM / MM: General concepts. Applications to enzymatic catalysis.

This theme is developed in 2 sessions, each lasting two hours, constituted again by a combination of expository class and practical class (Session 8-Session 9).
The objective of these two sessions is to combine what has been learned in Lesson 2 and 3, and to use the combination between quantum methods and classical methods to study in a hybrid way biological and supramolecular systems of considerable size where it is necessary to study their reactivity.
Before entering the hybrid methods, in Session 8, the fundamentals of the Docking technique (rigid and flexible) are exposed, to show the student how to locate the active center of a protein or molecular structure where a certain ligand "fits" . The most used software packages and the main applications that this methodology can have for the study of chemical and / or biological systems are discussed. We will also talk very briefly about virtual screening, commenting on its bases at a general level, and the main applications where it is used, mainly in drug discovery. The teacher explains how to carry out a docking with the Autodock program through a graphical interface or through the command line using the Autodock Vina package. Next, the student carries out the same docking of a biological system with different ligands, both rigid and flexible, through the graphic interface (using the Autodock software) or through the command line (Autodock Vina).
In Session 9 , the fundamental bases of hybrid QM / MM methods are introduced and their applications to the study of reaction mechanisms in biological and supramolecular systems are presented. In these methods, a part of the system (where the atoms involved in breaking and bonding are placed) is represented quantumly (QM) while the rest of the system is treated in a classical way (MM). The teacher explains how to conduct a QM / MM study using the appropriate software. Then, the student applies the concepts explained to carry out the study of a reaction mechanism in the system previously used in the practical case of docking, using the QM / MM method.

RECOMMENDED BIBLIOGRAPHY:
Material deposited in the virtual classroom.
-Molecular Modeling. Principles and Applications (Ed Pearson Education, 2001), Andrew R. Leach
-Introduction to Computational Chemistry (Ed Wiley), Frank Jensen.
DOCKING:
http://autodock.scripps.edu/faqs-help/tutorial
http://vina.scripps.edu/manual.html
QM / MM:
http://www.gromacs.org/Documentation/How-tos/ QMMM
https://gaussian.com/oniom/

LESSON 1:
Material deposited in the virtual classroom.
Introduction to Computational Chemistry:
-Molecular Modeling. Principles and Applications (Ed Pearson Education, 2001), Andrew R. Leach
-Introduction to Computational Chemistry (Ed Wiley), Frank Jensen.
Introduction to Linux and Bash:
-https://computernewage.com/2018/09/16/scripting-linux-introduction/
-https://www.howtoforge.com/tutorial/linux-shell-scripting-lessons/
-https : //linuxconfig.org/bash-scripting-tutorial-for-beginners
Introduction to Python:
-https://www.python.org/about/gettingstarted/
-https://www.learnpython.org/en/
Molecular Viewers :
-http://cheminf.cmbi.ru.nl/molden/
-http://www.cambridgesoft.com/support/ProductHomePage.aspx?KBCatID=112
-http://www.ks.uiuc.edu/Training /Tutorials/vmd-index.html
-http://pymol.sourceforge.net/newman/user/toc.html
-https://avogadro.cc/

LESSON2:
Material deposited in the virtual classroom.
-IN Levine, Quantum Chemistry, 5th Ed., Pearson Education (2001).
- CJ Cramer, Essentials of Computational Chemistry, John Wiley & Sons (2002).
- F. Jensen, Introduction to Computational Chemistry, 2nd Edition, John Wiley & Sons (1999).
- PW Atckins, RS Friedman, Molecular Quantum Mechanics, 3rd Ed., Oxford Univ. Press (1997).
- PW Atkins, RS Friedman, Solutions Manual for Molecular Quantum. Oxford Univ. Press (1997).
- A. Szabo, NS Ostlund, Modern Quantum Chemistry. Introduction to Advanced Electronic Structure Theory, Dover Pub., Inc. (1996).
- T. Helgaker, P. Joergensen, J. Olsen, 'Molecular Electronic-Structure Theory', John Wiley & Sons (2000).
- J. Simons, J. Nichols, Quantum Mechanics in Chemistry, Oxford Univ. Press (1997).
- JB Foresman, Æleen Frisch, Exploring Chemistry with Electronic Structure Methods, 2nd Ed., Gaussian, Inc. (1995-96).

LESSON 3:
Material deposited in the virtual classroom.
-Molecular Modeling. Principles and Applications (Ed Pearson Education, 2001), Andrew R. Leach
-Introduction to Computational Chemistry (Ed Wiley), Frank Jensen.
MOLECULAR DYNAMICS:
http://www.gromacs.org/Documentation/Terminology/Molecular_Dynamics_Sim…
http://www.mdtutorials.com/gmx/
http://www.gromacs.org/Documentation/Tutorials
http://cgmartini.nl /index.php/tutorials

LESSON 4:
Material deposited in the virtual classroom.
-Molecular Modeling. Principles and Applications (Ed Pearson Education, 2001), Andrew R. Leach
-Introduction to Computational Chemistry (Ed Wiley), Frank Jensen.
DOCKING:
http://autodock.scripps.edu/faqs-help/tutorial
http://vina.scripps.edu/manual.html
QM / MM:
http://www.gromacs.org/Documentation/How-tos/ QMMM
https://gaussian.com/oniom/

BASIC SKILLS:

-Students should know how to use the knowledge acquired and their problem-solving capacity in new or little known environments within wider (or multidisciplinary) contexts related to their field of study.

-Students should know how to communicate their findings and the knowledge and underlying reasons underpinning them to specialised and non-specialised audiences in a clear and unambiguous way.

-Students should have the learning skills that allow them to carry on studying in such a way that should be mainly self-directed or autonomous.


GENERAL SKILLS:

-Know how to use the knowledge acquired for practical problem solving in the field of research and innovation, in the multidisciplinary context of biological chemistry and molecular materials.

-Be able to discuss and communicate ideas, in both oral and written form, to specialised and non-specialised audiences (congresses, conferences, etc.) in a clear and reasoned way.


-Have the skills that allow students to develop an autonomous method for studying and learning.

-Be capable of working in multidisciplinary teams and collaborating with other specialists, both nationally and internationally.


TRANSVERSAL SKILLS:

-Develop teamwork skills: cooperation, leadership and good listening skills. Adapt to multidisciplinary teams.

-Draft scientific and technical reports and defend them publicly.


-Apply the concepts, principles, theories and models related to Biological Chemistry and Molecular Materials to new or little known environments within multidisciplinary contexts.


SPECIFIC SKILLS:

-Be capable of comparing experimental data and theoretical assumptions in a critical manner.

-Know the physicochemical bases of biological processes.

-Gain technical skill for carrying out the structural characterization of molecules, biomolecules, supramolecules and nanoparticles and interpreting the experimental data obtained.

Attendance

Theoretical classroom classes: 10 hours
Seminars and practical classes of blackboard: 2 hours
Scheduled tutoring: 1 hour
Practical laboratory or computer classes: 8 hours
Oral exhibitions of the students supported by audiovisual material or lectures by visiting professors: 2 hours
Evaluation and / or examination: 3 hours

SUBTOTAL: 26 hours

Non-presential

Preparation of tests and directed works: 15 hours
Study and personal work of the student: 34 hours

SUBTOTAL: 49 hours

TOTAL: 75 hours

The expository sessions and the practical sessions will be combined in nine sessions of 2 hours of duration each one of them, as follows (EXP: expository hour; P: practical hour):

SESSION 1: EXP1 + EXP2
SESSION 2: EXP3 + P1
SESSION 3: EXP4 + P2
SESSION: 4 EXP5 + P3
SESSION: 5 EXP6 + P4
SESSION: 6 EXP7 + P5
SESSION: 7 EXP8 + P6
SESSION: 8 EXP9 + P7
SESSION: 9 EXP10 + P8

The lessons will be distributed in the following sessions:

Lesson 1: SESSION 1
Lesson 2: SESSION 2-5
Lesson 3: SESSION 6-7
Lesson 4: SESSION 8-9

The practical hours of the subject will be carried out in the following sessions:
Practice 1: SESSION 2-3
Practice 2: SESSION 4-5
Practice 3: SESSION 6-7
Practice 4: SESSION 8-9

Training activities in the classroom with the presence of the teacher

A) Theoretical-practical sessions: This subject is divided into nine sessions of 2 hours each. Each session combines expository and practical classes, as shown in the sheme of the previous section. This methodological scheme intends to replace the lectures where the student barely intervenes, by theoretical-practical sessions that encourage self-learning of the student, relating the assimilation of theoretical concepts to the resolution of problems and practical situations that could be found in their possible professional future.
During these sessions, the teachers will combine explanations of theoretical concepts, the approach and resolution of practical exercises with instructions directly related to the practice that the student will carry out within the same session. The teachers will have the support of audiovisual and computer media. A computer will be available to students, although it is recommended that they bring their own laptops, where they can install the programs used in the practices, and thus be used during non-presential work.
During each session, the student must carry out a practical part independently. For this, they will have a Reference Manual, which will include an introduction to computer work and, in particular, its application to computational calculations, as well as a script for each of the practices to be performed, which will consist of a brief presentation of the theoretical foundations of the practice and the indication of the calculations to be made and the results to be presented. The student will do the practices individually, and will present the results to be evaluated at the end of the sessions (2 hours of oral expositions of the students supported by audiovisual material).
Attendance at these nine sessions (Session 1-9) is mandatory. The absences must be documentary justified, accepting reasons of examination and health, as well as those cases contemplated in the current university regulations.

B) Seminars and practical blackboard classes:
The aim of these sessions is to resolve doubts about the theory, practices and exercises proposed in Bulletins 1-3, with the active participation of the student: delivery of exercises to the teacher, resolution of exercises in the classroom, etc. Attendance at these classes is mandatory.

C) Tutorials scheduled by teachers and coordinated by the Center. The aim of these sessions is to resolve any doubts that students may have regarding any content of the subject. Attendance to this class is not mandatory.

1. Attendance
Attendance at the 9 theoretical-practical sessions is mandatory. The absences must be documentary justified, accepting reasons of examination and health, as well as those cases contemplated in the current university regulations.

2. The evaluation will consist of two parts (% final grade):
2.1. Continuous evaluation (50%), consisting of:
i. Tests delivered to the teacher (15%)
ii. Computer practices (20%)
iii. Oral exposure (15%)

2.2. Final exam (50%)
The final exam will consist of test-type questions in which the level of knowledge acquired during the course will be evaluated (duration: 3 hours).

The qualification of the student will not be inferior to the one of the final examination nor to the obtained one pondering it with the one of continuous evaluation. In any case, to pass the subject, it will be an essential requirement to have the qualification of APTO in computer practices. Repeating students will have the same attendance regime for classes as those who take the subject for the first time.

Preparation of tests and directed works: 15 hours
Study and personal work of the student: 34 hours

SUBTOTAL: 49 hours

Recommendations for the study of the subject:
-It is mandatory to attend the theoretical-practical sessions.
-It is advisable to attend the Seminars and Tutorials Sessions.
-It is recommended the use of own laptops, for the installation of all the programs used in the subject.
-It is advisable to make some of the tutorials available online and indicated in this guide Teacher to increase the skill in the programs used in the practices and to reinforce the contents.
- During the study of a topic, it is useful to make a summary of the important points, identifying the concepts and the basic equations, making sure to know both their meaning and the conditions in which they can be applied.
-Any questions that may arise should be consulted with the teachers.

Recommendations for the evaluation:
The student must study the theory presented in each subject, using the material made available in the virtual classroom and the recommended bibliography and clarify any doubts that may arise in this regard with the teachers of the subject.
Subsequently, the student must solve problems related to the theory, starting with those proposed in class, and acquire fluency in the handling of the different computer simulation software packages. Those students who encounter significant difficulties when working on the proposed activities should comment to the teachers, with the aim that they can analyze the problem and help solve these difficulties.

Recommendations for recovery:
Teachers will help students who do not pass the subject, studying with them the difficulties encountered in learning the contents and can provide them with additional material to reinforce the learning of the subject.