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Gene & Protein in Disease In silico application of the CoM method

distance. The conclusion was derived by measuring the the convergent state. In such cases, prior-convergent
average of the CoM distance between the ligands and oscillations may easily suppress the impact of relative flat
SARS-CoV-2 main protease, during the course of 100- and convergent CoM distance amplitudes. Having them
ns MD simulation. The average of the CoM distance for averaged during the course of the whole MD simulation,
erylosides B was less than the average CoM distance for a wrong conclusion about the real direction of the affinity
lopinavir, which was taken as a clue that erylosides B binds change may be derived.
the SARS-CoV-2 main protease more effectively than To explain this situation better, let’s take two random
lopinavir, demonstrating higher inhibitory potential. systems A and B, with a total of eight CoM distance
Kumar et al. analyzed pi-stacking interaction between snapshots [nm], such as the first five are prior-convergent
3
Omicron receptor binding domain (RBD) Tyr501 and samples and the last three convergent: A={4; 4.5; 3.9; 3.8; 3.5;
human angiotensin-converting enzyme 2 (hACE2) 2.8; 2.75; 2.75} and B={3; 4; 4.5; 3; 3.2; 2.83; 2.82; 2.81}. By
Tyr41, as N501Y is one of the key mutations responsible considering the integral systems’ dynamics, upon the eight
for increased infectivity. 1,7,8 The CoM distance between CoM distance snapshots, the average CoM distance in the
the aromatic rings has been measured, which in the system A is higher than the one in the system B (3.5 nm vs.
case of pi-stacking interaction should not exceed 5 Å. 3.27 nm), which is interpreted in terms of reduced binding
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Such interaction is going to increase hACE2–surface affinity between the units in system A in comparison to the
glycoprotein (S-protein) binding affinity that will ultimately binding affinity between the units in system B. However,
increase infectivity. The average CoM distance between the opposite of the previous conclusion is actually true, as
aromatic rings of <5 Å in most of the conformations the average CoM distance throughout the convergent state
confirmed pi-stacking interaction between hACE2 Tyr41 upon the last three snapshots in the system A is less than
and Omicron RBD Tyr501, which has been regarded as the one in system B (2.77 nm versus 2.82 nm).
one of the reasons that explains the higher viral load and An intuitive solution to this problem is to compute the
infectivity of the N501Y-bearing SARS-CoV-2 variant.
average of the intermolecular CoM distance during the
Apart from the CoM distance method, which is convergent phase only and neglect the non-convergent
the main point of discussion in this study, researchers system’s behavior. It is of crucial importance in the cases
have also exploited additional in silico methods, such as where the individual impact of a particular mutation or
residue fluctuation, radius of gyration, solvent accessible a combination of a few mutations need to estimated, a
surface area and free energy landscapes, in order to situation in which the wild-type and mutant complex share
analyze the fundamental properties of SARS-CoV-2 very similar CoM distance plots.
proteins’ interactions 10,11 or evaluate the structural impact
of selected mutations. 12-14 Docking studies proved to be 2. Method overview
especially useful in selecting highly effective SARS-CoV-2 Let W be the wild-type heterodimer and M the mutant of
inhibitors. Stability of the formed complexes has been used W. W can be retrieved from the Protein Data Bank in.pdb
as a prime criterion to evaluate the inhibitory potential of format. Molecular visualization software, such as PyMol,
each candidate. Ahamad et al. found that anidulafungin can be used to mutate the wild-type heterodimer W to M.
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has the same neutralizing capacity as the well-studied Initially, both systems, W and M, need to be well-prepared
lopinavir. In another study, Ahamad et al. evaluated and energetically optimized within self and toward the
11
the efficiency of several N-protein targeted antagonists solvent that will guarantee that the systems are stable enough
and suggested 4E1RCat and TMCB as candidate drugs. to undergo the process of MD simulation. The details of
MD simulations have also been used to study the impact systems’ preparation steps are described in the section 3. The
of selected mutations. In silico findings that RBD and method is formally described in the next section (Figure 1).
Heptad Repeat 1 mutations can impose major structural
destabilization, affecting pre-binding protein structure, 2.1. Formal description of the method
which may negatively impact current therapeutic efforts,
have been presented in several papers. 12-14 The CoM of a monomer of n atoms at positions r and
j
masses: m ,m ,…,m can be computed as:
In some instances, using the average of the 1 2 n
intermolecular CoM distance during the whole MD n i1 mr
ii
simulation, may give rise wrong conclusions related to com n m (I)
2,3
the binding affinity change. The reason for this is the fact i1 i
that molecules usually exhibit sudden and sharp local and where com is an oscillating point in the time (t):
global movements, one relative to another, before entering com(t)=(x(t),y(t),z(t),z(t)).

Volume 3 Issue 1 (2024) 2 https://doi.org/10.36922/gpd.2657