This discussion brings in a very interesting related question: what is 
the uncertainty of the model given the map?

The suggestion of using multiple maps to do the fitting looks a bit like 
cross-validation. I think there was a relatively recent paper (but I 
cannot remember which one now) suggesting to independently model each 
one of the halves and then comparing the two models (this would be a 
2-fold cross validation). Another possibility was fitting multiple 
models to a single volume as in Herzik, M. A.; Fraser, J. S. & Lander, 
G. C. A Multi-model Approach to Assessing Local and Global Cryo-EM Map 
Quality. Structure, 2019, 27, 344-358.e3

At the moment this uncertainty is not normally calculated, probably 
because it takes a lot of effort, but hopefully this will improve in the 
future.

Kind regards, Carlos Oscar

El 10/09/2020 a las 16:02, Takanori Nakane escribió:
> Hi,
>
> This is a very important question but, as far as I know, there is no 
> consensus yet.
>
> I myself is uncomfortable using "modified" maps for refinement.
> To see the danger, consider two extreme cases as thought experiments.
>
> 1. A hypothetical program that completely ignores the input
>    and outputs our 1.22 Å apoferritin map. Of course this is nonsense, 
> but the
>    resolution evaluated by half-set FSC of the output would "improve".
>    This is an example of introduction of wrong prior knowledge.
>
> 2. Another hypothetical program that internally builds an atomic model 
> and outputs
>    a map calculated from the model. The output would show wonderful 
> density with holes
>    in aromatics. The half-set FSC and FSC against (your manually created)
>    model would both improve, but the new map would tell nothing new.
>
> Of course, existing density modification programs try to avoid these 
> issues
> but I don't know how well they are validated. Especially it is hard to 
> evaluate
> how universal neural networks are.
> (e.g. what happens if the input is very different from the training 
> cases?)
>
> One possibility would be:
>
> 1. refine an atomic model against the density modified half map 1
> 2. refine an atomic model against the original half map 1
> 3. calculate FSC between model 1 or 2 vs the ORIGINAL half map 2
>
> It the density modification procedure improved the atomic model,
> the FSC of model 1 vs the original half map 2 should be better than
> the FSC of model 2 vs the original half map 2.
>
> At least, one should deposit the original unfiltered half maps to EMDB 
> in addition
> to post-processed and/or density modified maps.
>
> Best regards,
>
> Takanori Nakane
>
> On 2020/09/10 13:57, Oosterheert, W. (Wout) wrote:
>> Dear all,
>>
>> I’ve been playing around with map postprocessing using DeepEMhancer, 
>> and I’m quite impressed by the results, especially for datasets that 
>> suffer from preferred-orientation.
>>
>> I recently obtained a 3.4 Å, gold-standard refinedmap using Relion, 
>> and subjected the unfiltered half-maps to postprocessing using 
>> DeepEMhancer. I then tried to refine my model against the 
>> DeepEMhancer-postprocessed map using Phenix Real-space refine. The 
>> model looks fine after refinement, but I noticed some strange values 
>> in the validation statistics:
>>
>>   * The model vs. data CC is only 0.73, whereas the CC is 0.84 when I 
>> refine against the Relion-postprocessed map.
>>   * The map to model FSC curve tails off very slowly, FSC = 0.5 is at 
>> 3.2 Å, and FSC = 0.3 at 2.2 Å. Is this type of behaviour expected?
>>
>> In the bioRxiv manuscript 
>> (https://www.biorxiv.org/content/10.1101/2020.06.12.148296v3), 
>>  manual model building using Coot is performed in the DeepEMhancer 
>> maps, but refinements are not mentioned. So my question is: 
>> can/should I run refinements against DeepEMhancer-postprocessed maps, 
>> or should I only use these maps to guide model building in Coot?
>>
>> Thanks,
>>
>> Wout
>>
>> /Wout Oosterheert; PhD Candidate; Crystal and Structural Chemistry; 
>> Bijvoet Center for Biomolecular Research; Utrecht University; The 
>> Netherlands/
>>
>>
>> ------------------------------------------------------------------------------------------------------------------------------------------------------ 
>>
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